Methods of Treating, Reducing the Incidence of, and/or Preventing Ischemic Events

ABSTRACT

Methods of treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing percutaneous coronary intervention (PCI), comprising administering to the patient a pharmaceutical composition comprising cangrelor. The method may further comprise administering an additional therapeutic agent to the patient, the additional therapeutic agent comprising a P2Y 12  inhibitor. Pharmaceutical compositions useful for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI. The pharmaceutical compositions comprise cangrelor. Methods of preparing a pharmaceutical composition for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI, comprising admixing cangrelor with one or more pharmaceutically acceptable excipients. An ischemic event may include stent thrombosis, myocardial infarction, ischemia-driven revascularization, and mortality.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 13/792,056filed on Mar. 9, 2013, which is a continuation-in-part of U.S.application Ser. No. 12/943,717 filed on Nov. 10, 2010, which claimspriority to U.S. provisional application Ser. No. 61/260,361 filed onNov. 11, 2009, each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods of treating, reducing theincidence of, and/or preventing an ischemic event in a patientundergoing percutaneous coronary intervention (PCI), comprisingadministering to the patient a pharmaceutical composition comprisingcangrelor. The methods may further comprise administering an additionaltherapeutic agent to the patient, the additional therapeutic agentcomprising a P2Y₁₂ inhibitor. The present invention also relates topharmaceutical compositions useful for treating, reducing the incidenceof, and/or preventing an ischemic event in a patient undergoing PCI. Thepharmaceutical compositions comprise cangrelor. The present inventionfurther relates to methods of preparing a pharmaceutical composition fortreating, reducing the incidence of, and/or preventing an ischemic eventin a patient undergoing PCI, comprising admixing cangrelor with one ormore pharmaceutically acceptable excipients. An ischemic event mayinclude stent thrombosis, myocardial infarction, ischemia-drivenrevascularization (IDR), and mortality.

BACKGROUND OF THE INVENTION

PCI is a procedure that opens narrowed arteries that supply heart musclewith blood. PCI with stent implantation is widely used to reduce therisk of mortality or myocardial infarction in patients with acutecoronary syndromes and to reduce the burden of angina and improve thequality of life in patients with stable angina.¹ However, thromboticcomplications during PCI are a major concern, particularly if theprocedure involves implantation of a stent, which can induce plateletadhesion, activation and thrombus formation on or near the stent.² Thus,antiplatelet therapies are an important adjunct to PCI.³ ¹ Mehta S R, etal., JAMA 2005; 293:2908-17; De Bruyne B, at al., N Engl J Mod 2012;367:991-1001 [Erratum, N Engl J Med 2012; 367:1768.]; Bhatt D L, JAMA2005; 293:2935-7; Bavry A A, at al., J Am Coll Cardiol 2006; 48:1319-25:and Bhatt D L, at al., JAMA 2004; 292:2096-104.² Windecker S, et al.,Circulation 2007; 116:1952-65; Maisel W H, N Engl J Mod 2007;356:981-4.³ Grüntzig A R, at al., N Engl J Med 1979; 301:61-8.

Inhibition of platelet adenosine diphosphate (ADP) receptor P2Y₁₂through pharmacotherapy has been demonstrated to improve cardiovascularoutcomes in patients undergoing PCI.⁴ Such antiplatelet therapies reducethe risk of ischemic events, particularly stent thrombosis.⁵ Yet, thereare several limitations regarding the use of orally administeredP2Y₁₂-receptor inhibitors. For instance, there is a delayed onset ofaction when these drugs are administered, even when given with a loadingdose,⁶ which is particularly problematic for patients who require urgentor periprocedural treatment. In addition, patients in the acute phase ofcardiovascular illness may have conditions such as nausea, impairedabsorption, or impaired perfusion that can limit drug bioavailability;in such patients the antiplatelet effect of oral antiplatelet agentssuch as clopidogrel may not be sufficient.⁷ Further, multiple studieshave now demonstrated that the pharmacokinetic and pharmacodynamiceffects of clopidogrel are highly variable⁸ and may be influenced bygenetic polymorphisms,⁹ which translate into differentialpharmacodynamic and therapeutic responses that lead to the notion ofclopidogrel “non-responders.”¹⁰ Moreover, many physicians refrain fromadministering clopidogrel prior to angiographic definition of coronaryanatomy, as this irreversible platelet inhibitor has been associatedwith an increased risk of perioperative bleeding if coronary arterybypass surgery is required rather than percutaneous revascularization.More potent oral ADP blockers have been tested and found to reduceischemic outcomes even further, but with increased rates of bleeding.¹¹⁴ Yusuf S, at al., N. Eng J Med 2001; 345:494-502; Mehta S R, et al.,Lancet 2001; 358:527-33; Sabatine M S, at al., N Engl J Med 2005;352:1179-89; and Steinhubl S R, at al., JAMA 2002; 288:2411-20 [Erratum,JAMA 2003; 289:987.].⁵ Yusuf O, at al., Nat Rev Cardiol 2011; 8:547-59;Wiviott S D, at al., N Engl J Med 2007; 357:2001-15; Wallentin at al., NEngl J Med 2009; 361:1045-57; and Bhatt D L, N Engl J Med 2007;357:2078-81.⁶ Meadows T A, ct al., Circ Res 2007; 100:1261-75.⁷Sou{hacek over (c)}ková L, at al., Eur J Clin Pharmacol 2013; 69:309-17and Heestermans A A, at al., Thromb Res 2008; 122:776-81.⁸ Gurbel P A,et al., J Am Coll Cardiol 2005; 45:1392-6 and Collet J P, at al., Lancet2009; 373:309-17.⁹ Mega J L, at al., N Engl J Med 2009; 360:354-62.¹⁰Gurbel P A, at al., Nature Clin Pract Cardiovasc Mod 2006; 3:387-95.¹¹Wiviott S D, at al., N Engl J Med 2007; 357:2001-15; Bhatt D L, N Engl JMed 2007; 357:2078-81; Bhatt D L, N Engl J Med 2009; 361:940-2;Wallentin L, at al., N Engl J Med 2009; 361:1045-57; and Schömig A, atal., N Engl J Med 2009; 361:1108-11.

Thus, despite advances in adjunctive pharmacotherapy, the concern ofischemic events in a patient undergoing PCI has not been eliminated.¹²Accordingly, there is a continuing need for a potent, fast-acting,reversible antiplatelet agent that effectively treats, reduces theincidence of, and/or prevents ischemic events without an excessive riskof bleeding. ¹² Stone G W, et al., N Engl J Med 2009; 360:1946-59 andBavry A A, et al., Lancet 2008; 3712134-33.

SUMMARY OF THE INVENTION

The present invention demonstrates how cangrelor may be utilized intreating, reducing the incidence of, and/or preventing an ischemicevent. An ischemic event may include stent thrombosis, myocardialinfarction, IDR, and mortality. An ischemic event can occur before,during, or after PCI.

An aspect of the present invention is directed to a method of treating,reducing the incidence of, and/or preventing an ischemic event in apatient undergoing PCI. The method comprises administering to thepatient a pharmaceutical composition comprising cangrelor. Thepharmaceutical composition may be administered before, during, and/orafter PCI, and through various routes of administration. For example,the pharmaceutical composition may be administered intravenously,including as a bolus and/or infusion. In addition, the pharmaceuticalcomposition may be administered to a patient undergoing PCI involvingstent implantation. The method of the present invention may treat,reduce the incidence of, and/or prevent an ischemic event during orafter PCI. In some instances, the method is not accompanied by asignificant increase in severe bleeding or the need for transfusions.

In certain embodiments of the invention, the method may further compriseadministering an additional therapeutic agent to the patient. Theadditional therapeutic agent may be administered separately from thepharmaceutical composition comprising cangrelor, either sequentially orconcurrently. Alternatively, the additional therapeutic agent may beadministered in the same pharmaceutical composition as cangrelor. Insome embodiments, the additional therapeutic agent comprises a P2Y₁₂inhibitor, such as clopidogrel, prasugrel, or ticagrelor. In alternativeembodiments, the additional therapeutic agent comprises bivalirudin.

Another aspect of the present invention is directed to a pharmaceuticalcomposition useful for treating, reducing the incidence of, and/orpreventing an ischemic event in a patient undergoing PCI. Thepharmaceutical composition comprises cangrelor and may further compriseone or more pharmaceutically acceptable excipients. In addition, thepharmaceutical composition may be a solid, liquid, or suspension. Thepharmaceutical composition of the present invention may be useful fortreating, reducing the incidence of, and/or preventing an ischemic eventthat occurs during or after PCI. In some instances, the pharmaceuticalcomposition does not lead to a significant increase in severe bleedingor the need for transfusions when administered to a patient undergoingPCI.

A further aspect of the present invention is directed to a method ofpreparing a pharmaceutical composition for treating, reducing theincidence of, and/or preventing an ischemic event in a patientundergoing PCI, comprising admixing cangrelor with a pharmaceuticallyacceptable excipient. The pharmaceutically acceptable excipient maycomprise NaCl, dextrose, mannitol, or a combination thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1—diagram showing trial design for the study described in Example1.

FIG. 2—diagram showing the primary modified intent-to-treat analysispopulation in the study described in Example 1.

FIGS. 3A, 3B and 3C—landmark analysis of Kaplan-Meier curves for theprimary efficacy endpoint (FIG. 3A), stent thrombosis (FIG. 3B), andmortality at 48 hours and 30 days (FIG. 3C) in the study described inExample 1.

FIG. 4—diagram showing transfusion rates for all patients (includingcoronary artery bypass graft) in subgroups at high risk of bleeding inthe study described in Example 1.

FIG. 5—diagram showing trial design for the study described in Example2.

FIGS. 6A and 6B—display the primary endpoint odds ratio (OR) data forkey subgroups in the study described in Example 2.

FIG. 7—diagram showing trial design for the study described in Example3.

FIG. 8—diagram showing the modified intention-to-treat population in thestudy described in Example 3.

FIGS. 9A and 9B—landmark analysis of Kaplan Meier curves for the primaryendpoint (FIG. 9A) and the key secondary end point of stent thrombosis(FIG. 9B) in the study described in Example 3.

FIG. 10—diagram showing the subgroup analysis of the primary efficacyend point in the study described in Example 3.

FIG. 11—diagram showing the subgroup analysis of Global Use ofStrategies to Open Occluded Coronary Arteries (GUSTO) severe or moderatebleeding in the study described in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that cangrelor, areversible, fast acting, adenosine triphosphate analogue inhibitor ofthe P2Y₁₂ ADP receptor, is effective in treating, reducing the incidenceof, and/or preventing an ischemic event. Thus, the present invention isdirected to a method of treating, reducing the incidence of, and/orpreventing an ischemic event in a patient undergoing PCI, comprisingadministering to the patient a pharmaceutical composition comprisingcangrelor. The present invention is also directed to a pharmaceuticalcomposition useful for treating, reducing the incidence of, and/orpreventing an ischemic event in a patient undergoing PCI, wherein thepharmaceutical composition comprises cangrelor and may further compriseone or more pharmaceutically acceptable excipients. Further, the presentinvention is directed to a method of preparing a pharmaceuticalcomposition for treating, reducing the incidence of, and/or preventingan ischemic event in a patient undergoing PCI, comprising admixingcangrelor with one or more pharmaceutically acceptable excipients.

Cangrelor

Cangrelor is a non-thienopyridine adenosine triphosphate analogue whichreversibly binds to and inhibits the P2Y₁₂ ADP receptor. Cangrelor isdirect-acting, reversible, and selective, and it has a short half-life.It is metabolized through dephosphorylation pathways and has a plasmahalf-life of 3-5 minutes; platelet function returns to normal within30-60 minutes of drug termination.¹³ When given as a bolus plusinfusion, it quickly and consistently inhibits platelets to a highdegree with normalization of platelet function shortly afterdiscontinuation. A phase 2 trial in patients undergoing PCI demonstrateddose-dependent platelet inhibition similar to that achieved withabciximab, less bleeding time prolongation, and more rapid return toplatelet function.¹⁴ The chemical structure of cangrelor is shown inFormula I. ¹³ Storey R F, et al., Br J Haematol 2000; 110:925-34.¹⁴Greenbaum A B, et al., Am Heart J 2006; 151:689.e1-10.

In each of the embodiments of the present invention, the term“cangrelor” encompasses the compound of Formula I, as well astautomeric, enantiomeric and diastereomeric forms thereof, and racemicmixtures thereof, and pharmaceutically acceptable salts of thesecompounds, including a tetrasodium salt. These alternative forms andsalts, processes for their production, and pharmaceutical compositionscomprising them, are well known in the art and set forth, for example,in U.S. Pat. No. 5,721,219. Additional disclosure relevant to theproduction and use of cangrelor may be found in U.S. Pat. Nos.5,955,447, 6,130,208 and 6,114,313, as well as in U.S. Appln.Publication No. 2006/0270607.

Ischemic Events

The present invention demonstrates how cangrelor may be utilized intreating, reducing the incidence of, and/or preventing an ischemicevent. An ischemic event may include stent thrombosis, myocardialinfarction, IDR, and mortality. An ischemic event can occur before,during, or after PCI.

Stent Thrombosis

In certain embodiments, the present invention relates to treating,reducing the incidence of, and/or preventing stent thrombosis in apatient undergoing PCI. Stent thrombosis may result from any meansrelated to the implantation, presence, or maintenance of the stent inthe vasculature of the patient. For example, stent thrombosis may beinduced by implantation of a stent into the patient or may develop overtime due to the presence of a stent, such as a bare-metal stent, adrug-eluting stent, or other type of stent. In some embodiments, stentthrombosis is defined in accordance with or derived from the AcademicResearch Consortium definition of stent thrombosis.¹⁵ In certainembodiments of the present invention, stent thrombosis may beintraprocedural stent thrombosis, acute stent thrombosis (<24 hours postimplantation), sub-acute stent thrombosis (>24 hours and <30 days postimplantation), late stent thrombosis (>30 days and <12 months postimplantation) or very late stent thrombosis (>12 months postimplantation). ¹⁵ Cutlip D E, et al., Circulation 2007; 115(17):2344-51.

Myocardial Infarction

In certain embodiments, the present invention relates to treating,reducing the incidence of, and/or preventing myocardial infarction in apatient undergoing PCI. Myocardial infarction may be any form ofmyocardial infarction, including acute myocardial infarction (first fewhours to 7 days), healing myocardial infarction (7 to 28 days), healedmyocardial infarction (29 days and beyond), acute non-ST-elevatedmyocardial infarction (NSTEMI), and acute ST-elevated myocardialinfarction (STEMI). In some embodiments, myocardial infarction isdefined in accordance with or derived from the universal definition ofmyocardial infarction.¹⁶ ¹⁶ Thygesen K, et al., Eur Heart J 200728:2525-38.

Myocardial infarction may arise during PCI, or may be induced by anymechanism, including implantation of a stent into the patient.Myocardial infarction may also be caused by stent thrombosis orocclusion of a coronary artery.

Ischemia-Driven Revascularization (IDR)

In certain embodiments, the present invention relates to treating,reducing the incidence of, and/or preventing IDR in a patient undergoingPCI. IDR refers to any type of intervention following PCI in which bloodflow through a vessel must be increased or re-established. Examples ofIDR include, but are not limited to, an additional PCI or surgery.

Mortality

In certain embodiments, the present invention relates to reducing theincidence of and/or preventing mortality in a patient undergoing PCI. Insome embodiments, mortality may be associated with other ischemicevents. For instance, mortality may be caused by stent thrombosis,occlusion of a coronary artery, and/or myocardial infarction.

Methods of Treating, Reducing the Incidence of, and/or Preventing anIschemic Event

An aspect of the present invention is methods of treating, reducing theincidence of, and/or preventing an ischemic event in a patientundergoing PCI, comprising administering to the patient a pharmaceuticalcomposition comprising cangrelor.

PCI may comprise balloon angioplasty without implantation of a stent, ormay also comprise the implantation of a stent. The stent may be abare-metal stent, or a drug-eluting stent, as known in the art.

Timing, Duration, and Routes of Administration of the PharmaceuticalComposition

A method of the present invention comprises administering thepharmaceutical composition before, during, and/or after PCI. Theadministration may continue for a short period of time, such as lessthan about an hour, or may be one or more hours. In some embodiments,the administration may continue for at least the duration of the PCI. Inother embodiments, the administration may continue after the PCI hasconcluded. In certain embodiments, the administration may continue forat least about 2 hours or the duration of the PCI procedure, whicheveris longer. In an additional embodiment, the administration may continuefor about 4 hours or longer.

A method may comprise administering the pharmaceutical compositionmultiple times before, during, and/or after PCI. For example,administration of the pharmaceutical composition may be for a shortperiod of time before the PCI, and then again once PCI has begun.

In certain embodiments, the method may comprise administering thepharmaceutical composition periodically after the PCI has concluded. Forinstance, the pharmaceutical composition may be administered once,twice, thrice or more times a day, once every two days, once every threedays, etc., and for weeks, months, or even years, after the PCI,particularly if the PCI involved stent implantation.

In additional embodiments, the method may comprise administering thepharmaceutical composition once the ischemic event is recognized ordiagnosed, or at the onset of symptoms of the ischemic event. Forexample, the pharmaceutical composition may be administered if symptomsof a myocardial infarction are observed. The pharmaceutical compositionmay be administered within a short period of time from the onset ofsymptoms of the ischemic event. The short period of time may range fromabout one or two minutes to about one or two hours.

In some embodiments, the method may comprise administering thepharmaceutical composition as a prophylaxis against an ischemic event,such as myocardial infarction. Patients appropriate for such preventioninclude any patient suspected of having early symptoms of the ischemicevent or other disease, or a condition that could lead to the ischemicevent against which the pharmaceutical compositions of the inventionwould be effective. The pharmaceutical composition may be administeredto the patient within a short period of time of when early or initialsymptoms of the ischemic event are detected.

Methods of the present invention may comprise administering thepharmaceutical composition concurrently or sequentially with at leastone additional therapeutic agent. The additional therapeutic agent maybe a P2Y₁₂ receptor inhibitor, such as clopidogrel, ticagrelor, orprasugrel, or the additional therapeutic agent may be a glycoproteinIIb/IIIa inhibitor. Alternatively, the additional therapeutic agent maybe aspirin. In some embodiments, the additional therapeutic agent may beadministered after the administration of cangrelor, either immediatelyafter or following a short period of time. For example, when cangreloris administered as a bolus followed by infusion, the additionaltherapeutic agent, such as clopidogrel, may be administered after theinfusion of cangrelor is complete.

The routes of administration of the methods of the present inventioninclude, for example, oral, sublingual, intranasal, intraocular, rectal,transdermal, mucosal, topical or parenteral administration. Parenteralmodes of administration include without limitation, intradermal,subcutaneous (s.c., s.q., sub-Q, Hypo), intramuscular (i.m.),intravenous (i.v.), intraperitoneal (i.p.), intra-arterial,intramedulary, intracardiac, intra-articular (joint), intrasynovial(joint fluid area), intracranial, intraspinal, and intrathecal (spinalfluids). Any known device useful for parenteral injection or infusion ofdrug formulations can be used in the methods of the present invention.In noted aspects and embodiments of the present invention,administration is via parenteral administration, preferably intravenousadministration, or oral administration.

When administered intravenously, the pharmaceutical compositioncomprising cangrelor may be administered as a bolus, as a continuousinfusion, or as a bolus followed by a continuous infusion. For example,the pharmaceutical composition may be administered prior to PCI as abolus, and may be administered during PCI as a continuous infusion.

Doses of cangrelor in the pharmaceutical compositions administered inthe methods of the present invention may vary depending upon the statedgoals of the methods (treating, reducing the incidence of, and/orpreventing), the physical characteristics of the patient, thesignificance of the ischemic event, existence of related or unrelatedmedical conditions, the composition of the formulation and the meansused to administer the drug to the patient. The dose for a given patientwill generally be set by the judgment of the attending physician.

When administered as a bolus, a dose of about 5 to about 100 μg/kgcangrelor, such as between about 20 and about 40 μg/kg cangrelor, orabout 30 μg/kg cangrelor, is administered. When administered as acontinuous infusion, cangrelor may be administered at about 0.1 to about30 μg/kg/min, for example, between about 1 and about 10 μg/kg/min, orabout 4 μg/kg/min. One of ordinary skill in the art will understand thatthe dose may differ in the periods before PCI, during PCI and after PCI.

In certain embodiments, the method of the present invention comprisesadministering a bolus of about 30 μg/kg cangrelor, followed byadministering an infusion of about 4 μg/kg/min cangrelor.

When the pharmaceutical composition is administered orally, a dose ofbetween about 0.5 to about 100 mg/kg cangrelor or about 5 to about 30mg/kg cangrelor is administered per day. Oral administration may occuronce a day or multiple times per day.

In certain embodiments of the present invention, an additionaltherapeutic agent is administered in addition to the pharmaceuticalcomposition comprising cangrelor. When the additional therapeutic agentcomprises clopidogrel, it may be administered orally with a dose ofclopidogrel from about 75 mg to about 600 mg.

Patients

As used herein, a “patient” upon which the methods of the presentinvention may be practiced refers to an animal, such as a mammalian oran avian species, including a human, a non-human primate, a horse, acow, a sheep, a goat, a dog, and a cat. Such patients may have anischemic event, such as stent thrombosis, myocardial infarction, IDR, ormortality.

In view of the fact that the patients upon which some of the methods ofthe present invention are being practiced have underlying healthconditions that require PCI, one of ordinary skill in the art willunderstand that the patients may have various additional physicalcharacteristics related to such underlying health conditions. Forexample, in each of the embodiments of the present invention, thepatient may have a condition selected from the group consisting ofSTEMI, NSTEMI, stable angina, unstable angina, and acute coronarysyndrome. The patient may be of any age, gender, or weight. The patientmay have received different therapeutic agents, such as a periproceduralglycoprotein IIb/Ilia inhibitor, periprocedural unfractionated heparin(UFH), periprocedural low-molecular-weight heparin (LMWH),periprocedural bivalirudin, or periprocedural clopidogrel.

To further characterize the patients to which the methods of the presentinvention may be applied, it is noted that the patient may have suffereda stroke, or may have diabetes mellitus, hypertension, hyperlipidemia, amyocardial infarction, or may have a family history of coronary arterydisease (CAD). The patient may have undergone percutaneous transluminalcoronary angioplasty (PTCA), PCI, or coronary artery bypass graft(CABG). The patient may have congestive heart failure, peripheralarterial disease (PAD), or stent thrombosis in more than one artery orvein. Further, the patient may be on periprocedural medications such asclopidogrel, bivalirudin, unfractionated heparain, low-molecular-weightheparin, fondaparinux, or aspirin.

Results of the Methods

Each of the methods recited in the present invention may include theadditional step of measuring the effectiveness of the administration ofthe pharmaceutical composition comprising cangrelor, including thetiming, duration, and route of administration of the pharmaceuticalcomposition. The measurement may include the effectiveness of theadministration of any additional therapeutic agent. In one example, thisadditional step may be performed about 0.5 to about 24 hours afteradministration is complete. Characteristics that are representative ofeffectiveness include, for example, an increase in luminal diameterwithin a stent, a decrease in the size of the stent thrombus, and adecreased incidence of myocardial infarction.

Pharmaceutical Compositions Useful for Treating, Reducing the Incidenceof, and/or Preventing Ischemic Events

An aspect of the present invention is directed to a pharmaceuticalcomposition useful for treating, reducing the incidence of, and/orpreventing an ischemic event in a patient undergoing PCI. Thepharmaceutical composition comprises cangrelor, and may further compriseone or more pharmaceutically acceptable excipients. The pharmaceuticalcomposition may be administered according to any of the methods of thepresent invention described above.

Pharmaceutically Acceptable Excipients

These pharmaceutical compositions may comprise one or morepharmaceutically acceptable excipients including, but not limited to,carriers, diluents, stabilizing agents, solubilizing agents,surfactants, buffers, antioxidants, preservatives, tonicity agents,bulking agents, lubricating agents, emulsifiers, suspending or viscosityagents, fillers, disintegrating agents, binding agents, wetting agents,lubricating agents, antibacterials, chelating agents, sweeteners,perfuming agents, flavouring agents, coloring agents, administrationaids, and combinations thereof. Particular excipients include, but arenot limited to, cornstarch or gelatin, lactose, sucrose, dextrose,microcrystalline cellulose, kaolin, mannitol, sorbitol, dicalciumphosphate, sodium chloride, alginic acid, croscarmellose sodium, sodiumstarch glycolate, glycerol, ethanol, propylene glycol, polysorbate 80(Tween-80™), poly(ethylene)glycol 300 and 400 (PEG 300 and 400),PEGylated castor oil (e.g. Cremophor EL), poloxamer 407 and 188,cyclodextrin or cyclodextrin derivatives (including HPCD((2-hydroxypropyl)-cyclodextrin) and (2-hydroxyethyl)-cyclodextrin),hydrophilic and hydrophobic carriers, and combinations thereof.Hydrophobic carriers include, for example, fat emulsions, lipids,PEGylated phospholipids, polymer matrices, biocompatible polymers,lipospheres, vesicles, particles, and liposomes. In certain embodiments,the pharmaceutical compositions may comprise polyols, such as sorbitol,lactose, sucrose, inositol or trehalose.

The pharmaceutical compositions of the present invention may beformulated for the route by which they are administered to the patients,which include solids, liquids, and suspensions. For example, if thepharmaceutical composition is formulated for IV administration, thepharmaceutical composition may comprise an intravenous fluid, whichincludes, but is not limited to, water-for-injection (WFI),physiological saline, 0.9% NaCl, phosphate buffered saline, 5% dextrosein water, and 0.002% polysorbate 80 in water or Ringer's™ solution. Ifthe pharmaceutical composition is formulated for intramuscularadministration, the pharmaceutical composition may comprise anintravenous fluid, which includes, but is not limited to, WFI,physiological saline, 0.9% NaCl, phosphate buffered saline, and 5%dextrose in water.

If the pharmaceutical composition is formulated for oral administration,the pharmaceutical composition may comprise excipients that include, butare not limited to diluents (e.g., sodium and calcium carbonate, sodiumand calcium phosphate, and lactose), binding agents (e.g., acacia gum,starch, gelatin, sucrose, polyvinylpyrrolidone (Povidone), sorbitol,tragacanth, methylcellulose, sodium carboxymethylcellulose,hydroxypropyl methylcellulose, and ethylcellulose), fillers (e.g.,calcium phosphate, glycine, lactose, maize-starch, sorbitol, orsucrose), wetting agents, lubricating agents (e.g., metallic stearates,stearic acid, polyethylene glycol, waxes, oils, silica and colloidalsilica, silicon fluid or talc), disintegrating agents (e.g., potatostarch, corn starch and alginic acid), flavouring agents (e.g.peppermint, oil of wintergreen, fruit flavoring, bubblegum, and thelike), and coloring agents. Excipients may also include coatings such asglyceryl monostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract. For oral use, the pharmaceutical composition maybe made in the form of a tablet, capsule, suspension or liquid syrup orelixir, wafers and the like.

Preparing Pharmaceutical Compositions

The pharmaceutical compositions of the present invention may be preparedby admixing cangrelor with the one or more pharmaceutically acceptableexcipients. Methods of admixing and devices useful for admixing areknown in the art.

In certain embodiments, cangrelor and the one or more pharmaceuticallyacceptable excipients are dissolved and then admixed. The resultingmixture may be dried, such as through lyophilization, to form a solidpharmaceutical composition, or the resulting mixture may remain insolution form as a liquid pharmaceutical composition. In someembodiments, the solid pharmaceutical composition may be solubilized inan intravenous fluid before administration, for example, as a bolus orinfusion.

In some embodiments, the pharmaceutical composition is prepared bydissolving and admixing cangrelor, mannitol, sorbitol, and optionallysodium hydroxide, and then lyophilizing the mixture. Prior toadministration, the lyophilized mixture is dissolved in an intravenousfluid such as WFI or physiological saline.

The present invention will now be further described by way of thefollowing non-limiting examples, which further illustrate the presentinvention; such examples are not intended, nor should they beinterpreted, to limit the scope of the present invention.

Example 1 Intravenous Platelet Blockade with Cangrelor Versus PlaceboDuring Percutaneous Coronary Intervention

In this example, the efficacy of cangrelor versus placebo was examinedwhen administered to patients during percutaneous coronary intervention(PCI).

Patients were enrolled at 218 sites in 18 countries from October 2006 toMay 2009. Patients were randomized in a double-blind,placebo-controlled, double-dummy design to receive either (i) placebobolus and infusion or (ii) cangrelor 30 μg/kg bolus and 4 μg/kg/mininfusion for the duration of PCI, with a minimum infusion duration of 2hours and a maximum of 4 hours. Patients in the placebo arm of the trialreceived 600 mg of clopidogrel at the end of the procedure, whilepatients in the cangrelor arm received 600 mg of clopidogrel after theend of the cangrelor infusion (FIG. 1).

The inclusion criteria for the trial were as follows: age ≧18 years;diagnostic coronary angiography revealing atherosclerotic lesion(s)amenable to PCI with or without stent implantation; and evidence ofeither non-ST-segment elevation myocardial infarction or unstableangina. Stable angina was initially allowed at the beginning of thetrial prior to a protocol amendment. The diagnosis of non-ST-segmentelevation myocardial infarction required troponin I or T greater thanthe upper limit of normal within 24 hours of randomization (or iftroponin results were unavailable at that time, creatinekinase-myocardial band isoenzyme [CK-MB] greater than the upper limit ofnormal). The diagnosis of unstable angina required ischemic chestdiscomfort occurring at rest and lasting ≧10 minutes within the 24 hoursprior to randomization and dynamic electrocardiographic changes; age ≧65years and/or diabetes mellitus were also required.

The exclusion criteria included the following: prior thienopyridine usein the past 7 days, planned staged PCI procedure where the second stagewould occur ≦30 days after the first PCI, admission planned for <12hours following PCI, ST-segment elevation myocardial infarction within48 hours of randomization, known or suspected pregnancy, lactatingfemales, increased bleeding risk (ischemic stroke within the last yearor any previous hemorrhagic stroke), intracranial tumor, cerebralarteriovenous malformation, intracranial aneurysm, recent (<1 month)trauma or major surgery (including coronary artery bypass grafting),current warfarin use, active bleeding, known International NormalizedRatio >1.5, past or present bleeding disorder, platelet count<100,000/μL, severe hypertension (systolic blood pressure >180 mm Hg ordiastolic blood pressure >110 mm Hg), fibrinolytic therapy orglycoprotein IIb/IIIa inhibitor use in the 12 hours precedingrandomization.

The primary efficacy endpoint was the composite of mortality, myocardialinfarction, or ischemia-driven revascularization at 48 hours. Theprimary analysis was performed on a modified intent-to-treat population.Confirmatory analyses were performed on an intent-to-treat population.Secondary endpoints included the individual rates of mortality,myocardial infarction, new Q-wave myocardial infarction, ischemia-drivenrevascularization, abrupt vessel closure, or stroke at 48 hours.Mortality at 30 days and 1 year was also recorded. The clinical eventscommittee adjudicated myocardial infarction, Q-wave myocardialinfarction, ischemia-driven revascularization, stent thromboses, andstroke (ischemic or hemorrhagic). The definition of stent thrombosis wassimilar to the Academic Research Consortium definition of definite stentthrombosis. After review of the prespecified analyses, two exploratoryendpoints less reliant on periprocedural biomarker ascertainment wereexamined. The exploratory endpoints, which were composed of prespecifiedand adjudicated endpoints, were the composite of mortality, Q-wavemyocardial infarction, or ischemia-driven revascularization and thecomposite of mortality, Q-wave myocardial infarction, or stentthrombosis. Bleeding and adverse events through 48 hours were compared.

Statistical analyses—All efficacy analyses were performed on themodified intent-to-treat population, defined as all randomized patientswho received at least one dose of study drug and underwent the indexPCI. All safety-related analyses were performed on the safetypopulation, which included all patients who received at least one doseof assigned study drug. Patients in the safety analyses were assigned toa treatment arm based on treatment actually received, not as randomized.Intent-to-treat analyses are also presented for full disclosure ofresults. All statistical tests were two-tailed using a level ofsignificance of 0.05. The primary endpoint comparison between thecangrelor and placebo arms was performed by calculating an odds ratio(OR) with accompanying 95% confidence intervals (CI) using logisticregression. Logistic regression was also used to analyze the majority ofthe remaining secondary endpoints. The trial had 85% power to detect a25% reduction in the primary endpoint, assuming a 7.7% event rate in theplacebo arm, with a projected sample size of 6400 patients.

A total of 5362 patients were included in the intent-to-treatpopulation; of these, 5301 formed the primary modified intent-to-treatanalysis population (FIG. 2). There were 61 patients who were notincluded because they did not receive study drug or undergo PCI.Baseline characteristics were well-matched in the two groups (Table 1).

TABLE 1 Baseline characteristics for ITT, MITT, and Safety populationsITT MITT Cangrelor Clopidogrel Cangrelor Clopidogrel Baselinecharacteristics (N = 2693) (N = 2669) (N = 2656) (N = 2645) Age, yrs63.0 (54.0, 71.0) 63.0 (54.0, 71.0) 63.0 (54.0, 71.0) 63.0 (54.0, 71.0)Sex, No. (%) Male 1938 (72.0) 1877 (70.3) 1909 (71.9) 1863 (70.4) Female755 (28.0) 792 (29.7) 747 (28.1) 782 (29.6) Race, No. (%) White 2039(76.0) 2024 (76.0) 2015 (76.1) 2006 (76.0) Asian 482 (18.0) 476 (17.9)475 (17.9) 473 (17.9) Black 80 (3.0) 73 (2.7) 75 (2.8) 72 (2.7) Hispanic75 (2.8) 85 (3.2) 74 (2.8) 84 (3.2) Other 8 (0.3) 5 (0.2) 8 (0.3) 5(0.2) Weight, kg 80.0 (70.0, 92.0) 80.0 (70.0, 92.0) 80.0 (70.0, 92.0)80.0 (70.0, 92.0) Height, cm 170.0 (163.0, 176.0) 170.0 (163.0, 176.0)170.0 (163.0, 176.0) 170.0 (163.0, 176.0) Stable angina, No. (%) 145(5.4) 142 (5.3) 139 (5.2) 140 (5.3) Unstable angina, No. (%) 949 (35.2)918 (34.4) 939 (35.4) 909 (34.4) NSTEMI, No. (%) 1599 (59.4) 1609 (60.3)1578 (59.4) 1596 (60.3) Medical history, No. (%) Diabetes mellitus 828(30.8) 868 (32.6) 812 (30.6) 862 (32.6) Current smoker 850 (31.8) 806(30.4) 842 (31.9) 799 (30.4) Hypertension 1994 (74.3) 1979 (74.5) 1972(74.5) 1962 (74.5) Hyperlipidemia 1342 (53.5) 1347 (54.0) 1324 (53.6)1332 (53.9) Stroke/TIA 162 (6.0) 160 (6.0) 159 (6.0) 138 (6.0) Familyhistory of CAD 918 (36.4) 901 (36.0) 902 (36.2) 890 (35.9) MI 645 (24.1)683 (25.7) 640 (24.2) 679 (25.8) PTCA/PCI 381 (14.2) 411 (15.5) 374(14.1) 409 (15.5) CABG 203 (7.5) 223 (8.4) 199 (7.5) 221 (8.4)Congestive HF 210 (7.8) 192 (7.2) 206 (7.8) 191 (7.2) PAD 126 (4.8) 143(5.5) 122 (4.7) 142 (5.5) Periprocedural medications, No (%) Bivalirudin565 (21.0) 561 (21.0) 559 (21.0) 555 (21.0) UFH 1714 (63.7) 1709 (64.1)1699 (64.0) 1695 (64.1) LMWH 487 (18.1) 501 (18.8) 481 (18.1) 497 (18.8)GP IIb/IIIa 245 (9.1) 247 (9.3) 241 (9.1) 244 (9.2) Study treatmentNumber of target vessels, No. (%) 1 2231 (83.7) 2211 (83.3) 2218 (83.6)2201 (83.3) 2 414 (15.5) 412 (15.5) 414 (15.6) 412 (15.6) 3 19 (0.7) 29(1.1) 19 (0.7) 29 (1.1) Drug-eluting stent, No. (%) 1037 (38.9) 1023(38.6) 1033 (38.9) 1021 (38.6) Non-drug-eluting stent, No. (%) 1514(56.8) 1515 (57.1) 1509 (56.9) 1510 (57.1) Angiographic complications(site reported) Threatened abrupt closure 10 (0.4) 9 (0.3) 10 (0.4) 9(0.3) Unsuccessful procedure 84 (3.1) 97 (3.7) 81 (3.1) 95 (3.6) Abruptvessel closure 13 (0.5) 16 (0.6) 13 (0.5) 16 (0.6) New thrombus orsuspected thrombus 14 (0.5) 15 (0.6) 14 (0.5) 15 (0.6) Acute stentthrombosis 1 (0.0) 5 (0.2) 1 (0.0) 5 (0.2) Need for urgent CABG 5 (0.2)4 (0.2) 5 (0.2) 3 (0.1) IV study drug administered, No. (%) 2663 (98.9)2649 (99.3) 2656 (100.0) 2645 (100.0) Bolus administered, No. (%) 2663(98.9) 2649 (99.3) 2656 (100.0) 2645 (100.0) Infusion administered, No.(%) 2659 (98.7) 2649 (99.3) 2654 (99.9) 2645 (100.0) Duration ofinfusion, hrs 2.1 (2.0, 2.3) 2.1 (2.0, 2.3) 2.1 (2.0, 2.3) 2.1 (2.0,2.3) Oral study drug administered, No. (%) 2630 (97.7) 2626 (98.4) 2629(99.0) 2625 (99.2) Safety Cangrelor Clopidogrel Baseline characteristics(N = 2662) (N = 2650) Age, yrs 63.0 (54.0, 71.0) 63.0 (54.0, 71.0) Sex,No. (%) Male 1915 (71.9) 1866 (70.4) Female 747 (28.1) 784 (29.6) Race,No. (%) White 2017 (76.0) 2009 (76.0) Asian 477 (18.0) 474 (17.9) Black76 (2.9) 73 (2.8) Hispanic 75 (2.8) 84 (3.2) Other 8 (0.3) 5 (0.2)Weight, kg 80.0 (70.0, 92.0) 80.0 (70.0, 92.0) Height, cm 170.0 (163.0,176.0) 170.0 (163.0, 176.0) Stable angina, No. (%) 138 (5.2) 141 (5.3)Unstable angina, No. (%) 940 (35.3) 911 (34.4) NSTEMI, No. (%) 1584(59.5) 1598 (60.3) Medical history, No. (%) Diabetes mellitus 815 (30.6)862 (32.6) Current smoker 845 (31.9) 799 (30.3) Hypertension 1974 (74.4)1966 (74.5) Hyperlipidemia 1325 (53.5) 1335 (53.9) Stroke/TIA 160 (6.0)158 (6.0) Family history of CAD 907 (36.4) 891 (35.9) MI 641 (24.2) 680(25.7) PTCA/PCI 377 (14.2) 409 (15.5) CABG 200 (7.5) 221 (8.3)Congestive HF 208 (7.8) 191 (7.2) PAD 124 (4.8) 142 (5.5) Periproceduralmedications, No (%) Bivalirudin 561 (21.1) 556 (21.0) UFH 1701 (63.9)1699 (64.1) LMWH 484 (18.2) 497 (18.8) GP IIb/IIIa 242 (9.1) 244 (9.2)Study treatment Number of target vessels, No. (%) 1 2217 (83.6) 2202(83.3) 2 414 (15.6) 412 (15.6) 3 19 (0.7) 29 (1.1) Drug-eluting stent,No. (%) 1032 (38.9) 1022 (38.7) Non-drug-eluting stent, No. (%) 1509(56.9) 1510 (57.1) Angiographic complications (site reported) Threatenedabrupt closure 10 (0.4) 9 (0.3) Unsuccessful procedure 81 (3.1) 95 (3.6)Abrupt vessel closure 13 (0.5) 16 (0.6) New thrombus or suspectedthrombus 14 (0.5) 15 (0.6) Acute stent thrombosis 1 (0.0) 5 (0.2) Needfor urgent CABG 5 (0.2) 3 (0.1) IV study drug administered, No. (%) 2662(100.0) 2650 (100.0) Bolus administered, No. (%) 2662 (100.0) 2650(100.0) Infusion administered, No. (%) 2658 (99.8) 2650 (100.0) Durationof infusion, hrs 2.1 (2.0, 2.3) 2.1 (2.0, 2.3) Oral study drugadministered, No. (%) 2629 (98.8) 2627 (99.1) Variables are presented asmedian (25th, 75th) unless otherwise indicated. CABG denotes coronaryartery bypass grafting; CAD, coronary artery disease; GP, glycoprotein;HF, heart failure ITT, intent to treat; IV, intravenous; LMWH, lowmolecular weight heparin; MI, myocardial infarction; MITT, modifiedintent to treat; NSTEMI, non-ST-segment elevation myocardial infarction;PAD, peripheral artery disease; PCI, percutaneous coronary intervention;PTCA, percutaneous transluminal coronary angioplasty; TIA, transientischemic attack; UFH, unfractionated heparin.

The majority of patients were enrolled with non-ST-segment elevationmyocardial infarction (59.8%). During PCI, unfractionated heparin wasthe most frequently used antithrombin (63.9%) and glycoprotein IIb/IIainhibitors were used sparingly (9.2%). Drug-eluting stents were usedless often than bare metal stents (38.7% vs 56.9%). The time fromhospital admission to PCI was short (median of 7.9 hours [3.3, 24.1]).The primary endpoint occurred in 7.0% of patients receiving cangrelorand 8.0,% of patients receiving placebo (OR 0.87, 95% CI 0.71-1.07;P=0.17) (Table 2, FIG. 3A).

TABLE 2 48-hour endpoints for MITT, ITT, and Safety Populations MITTCangrelor Clopidogrel (N = 2656) (N = 2645) OR (95% CI) P ValueAdjudicated endpoints Mortality/MI/IDR (primary 185 (7.0)  210 (8.0) 0.867 (0.706, 1.065) 0.1746 endpoint) MI 177 (6.7)  191 (7.2)  0.917(0.742, 1.133) 0.4207 IDR 19 (0.7) 24 (0.9) 0.786 (0.430, 1.439) 0.4354All-cause mortality  6 (0.2) 18 (0.7) 0.330 (0.131, 0.833) 0.0190 Stroke 7 (0.3)  5 (0.2) 1.394 (0.442, 4.398) 0.5708 Stent thrombosis  5 (0.2)16 (0.6) 0.310 (0.113, 0.847) 0.0223 Q-wave MI  4 (0.2)  8 (0.3) 0.497(0.149, 1.652) 0.2538 Exploratory endpoints Mortality/Q-wave MI/IDR 23(0.9) 41 (1.6) 0.554 (0.332, 0.926) 0.0243 Mortality/Q-wave MI/Stent 13(0.5) 34 (1.3) 0.377 (0.199, 0.717) 0.0029 thrombosis ITT CangrelorClopidogrel (N = 2693) (N = 2669) OR (95% CI) P Value Adjudicatedendpoints Mortality/MI/IDR 187 (6.9)  213 (8.0)  0.859 (0.701, 1.054)0.1456 MI 177 (6.6)  192 (7.2)  0.906 (0.734, 1.120) 0.3632 IDR 19 (0.7)26 (1.0) 0.721 (0.398, 1.307) 0.2814 All-cause mortality  8 (0.3) 19(0.7) 0.415 (0.181, 0.950) 0.0374 Stroke  7 (0.3)  6 (0.2) 1.155 (0.388,3.442) 0.7954 Stent thrombosis  5 (0.2) 16 (0.6) 0.308 (0.113, 0.842)0.0218 Q-wave MI  4 (0.1)  9 (0.3) 0.439 (0.135, 1.428) 0.1713Exploratory endpoints Mortality/Q-wave MI/IDR 25 (0.9) 44 (1.7) 0.558(0.341, 0.915) 0.0207 Mortality/Q-wave MI/Stent 15 (0.6) 36 (1.4) 0.409(0.224, 0.749) 0.0038 thrombosis Safety Cangrelor Clopidogrel (N = 2662)(N = 2650) OR (95% CI) P Value Adjudicated endpoints Mortality/MI/IDR185 (7.0)  212 (8.0)  0.858 (0.699, 1.053) 0.1436 MI 176 (6.6)  193(7.3)  0.901 (0.729, 1.113) 0.3322 IDR 19 (0.7) 25 (0.9) 0.754 (0.414,1.373) 0.3561 All-cause mortality  7 (0.3) 18 (0.7) 0.385 (0.161, 0.924)0.0326 Stroke  7 (0.3)  5 (0.2) 1.394 (0.442, 4.396) 0.5712 Stentthrombosis  5 (0.2) 16 (0.6) 0.310 (0.113, 0.846) 0.0223 Q-wave MI  4(0.2)  9 (0.3) 0.441 (0.136, 1.435) 0.1738 Exploratory endpointsMortality/Q-wave MI/IDR 24 (0.9) 42 (1.6) 0.564 (0.341, 0.935) 0.0263Mortality/Q-wave MI/Stent 14 (0.5) 35 (1.3) 0.395 (0.212, 0.735) 0.0034thrombosis Variables are presented as no. (%) unless otherwiseindicated. CI denotes confidence interval; IDR, ischemia-drivenrevascularization; ITT, intent to treat; MI, myocardial infarction;MITT, modified intent to treat; OR, odds ratio.

There was no significant difference in overall myocardial infarction,Q-wave myocardial infarction, or ischemia-driven revascularization(Table 2). Rates of stent thrombosis were significantly lower withcangrelor (0.2% vs 0.6% [OR 0.31, 95% CI 0.11-0.85; P=0.022]) (FIG. 3B).The rate of mortality at 48 hours was significantly lower in thecangrelor arm (0.2% vs 0.7% [OR 0.33, 95% CI 0.13-0.83; P=0.019]),though by 30 days, this difference was no longer significant (Table 3,FIG. 3C).

TABLE 3 30-day endpoints for ITT, MITT, and Safety Populations ITTCangrelor Clopidogrel (N = 2693) (N = 2669) OR (95% CI) P ValueAdjudicated endpoints Mortality/MI/IDR 230 (8.6)  254 (9.6)  0.885(0.734, 1.067) 0.1999 MI 190 (7.1)  202 (7.6)  0.924 (0.752, 1.135)0.4515 IDR 37 (1.4) 49 (1.8) 0.743 (0.483, 1.142) 0.1752 All-causemortality 36 (1.3) 47 (1.8) 0.754 (0.487, 1.167) 0.2048 Stent thrombosis15 (0.6) 29 (1.1) 0.508 (0.272, 0.950) 0.0340 Q-wave MI  8 (0.3) 15(0.6) 0.526 (0.222, 1.242) 0.1425 Exploratory endpoints Mortality/Q-waveMI/IDR 69 (2.6) 94 (3.5) 0.718 (0.524, 0.984) 0.0396 Mortality/Q-waveMI/Stent 51 (1.9) 77 (2.9) 0.648 (0.453, 0.927) 0.0174 thrombosis MITTCangrelor Clopidogrel (N = 2656) (N = 2645) OR (95% CI) P ValueAdjudicated endpoints Mortality/MI/IDR 226 (8.5)  249 (9.5)  0.892(0.739, 1.078) 0.2365 MI 189 (7.1)  201 (7.6)  0.929 (0.756, 1.142)0.4831 IDR 37 (1.4) 46 (1.7) 0.796 (0.515, 1.231) 0.3054 All-causemortality 33 (1.2) 45 (1.7) 0.725 (0.461, 1.140) 0.1635 Stent thrombosis15 (0.6) 28 (1.1) 0.529 (0.282, 0.993) 0.0477 Q-wave MI  8 (0.3) 14(0.5) 0.566 (0.237, 1.352) 0.2003 Exploratory endpoints Martality/Q-waveMI/IDR 66 (2.5) 89 (3.4) 0.730 (0.528, 1.008) 0.0560 Mortality/Q-waveMI/Stent 48 (1.8) 73 (2.8) 0.647 (0.447, 0.935) 0.0203 thrombosis SafetyCangrelor Clopidogrel (N = 2662) (N = 2650) OR (95% CI) P ValueAdjudicated endpoints Mortality/MI/IDR 226 (8.5)  251 (9.5)  0.884(0.732, 1.067) 0.1999 MI 188 (7.1)  203 (7.7)  0.913 (0.743, 1.122)0.3887 IDR 37 (1.4) 47 (1.8) 0.779 (0.504, 1.202) 0.2584 All-causemortality 34 (1.3) 45 (1.7) 0.747 (0.477, 1.170) 0.2024 Stent thrombosis15 (0.6) 28 (1.1) 0.529 (0.282, 0.993) 0.0475 Q-wave MI  8 (0.3) 15(0.6) 0.528 (0.224, 1.248) 0.1455 Exploratory endpoints Mortality/Q-waveMI/IDR 67 (2.5) 90 (3.4) 0.732 (0.531, 1.010) 0.0572 Mortality/Q-waveMI/Stent 49 (1.8) 74 (2.8) 0.651 (0.452, 0.938) 0.0212 thrombosisVariables are presented as no. (%) unless otherwise indicated. CIdenotes confidence interval; IDR, ischemia-driven revascularization;ITT, intent to treat; MI, myocardial infarction; MITT, modified intentto treat; OR, odds ratio.

Somewhat counterintuitively, in the subgroup of 1659 patients enrolledwithout baseline troponin elevation, the primary efficacy endpoint wasreduced with cangrelor from 7.2% to 4.6% (OR 0.62, 95% CI 0.41, 0.95;P=0.0266). Therefore, exploratory analyses were performed in the overallstudy population examining the following two clinical endpoints:mortality, Q-wave myocardial infarction, or stent thrombosis; andmortality, Q-wave myocardial infarction, or ischemia-drivenrevascularization. These endpoints were significantly reduced in favorof cangrelor.

The rates of Thrombolysis in Myocardial Infarction (TIMI) major or minoror Global Utilization of Streptokinase and Tissue Plasminogen Activatorfor Occluded Coronary Arteries (GUSTO) severe or moderate bleeding werenot significantly different between the groups, though the rates ofAcute Catheterization and Urgent Intervention Triage Strategy (ACUITY)major and minor bleeding and of GUSTO mild bleeding were significantlyhigher with cangrelor (Table 4).

TABLE 4 48-hour bleeding events for safety population Cangrelor PlaceboOdds Ratio Bleeding Events (N = 2662) (N = 2650) (95% CI) P Value Accesssite bleeding requiring 8 (0.3) 10 (0.4)  0.796 (0.314, 2.019) 0.6307radiologic or surgical intervention Hematoma ≧5 cm at puncture site 115(4.3)  71 (2.7)  1.640 (1.214, 2.216) 0.0013 Intracranial hemorrhage 2(0.1) 1 (0.0) 1.992 (0.180, 21.978) 0.5738 Intraocular 0 (0.0) 0 (0.0)Reoperation for bleeding 1 (0.0) 1 (0.0) 0.995 (0.062, 15.924) 0.9975Retroperitoneal 2 (0.1) 1 (0.0) 1.992 (0.180, 21.978) 0.5738 Ecchymosis95 (3.6)  57 (2.2)  1.684 (1.207, 2.349) 0.0022 Epistaxis 6 (0.2) 12(0.5)  0.497 (0.186, 1.325) 0.1622 Hematoma <5 cm at puncture site 150(5.6)  119 (4.5)  1.270 (0.992, 1.626) 0.0577 Oozing at puncture site125 (4.7)  91 (3.4)  1.385 (1.052, 1.825) 0.0204 Thrombocytopenia 2(0.1) 3 (0.1) 0.663 (0.111, 3.973) 0.6532 Hemodynamic compromise 7 (0.3)5 (0.2) 1.395 (0.442, 4.400) 0.5704 Any blood transfusion 26 (1.0)  16(0.6)  1.624 (0.869, 3.034) 0.1285 Any platelet transfusion 4 (0.2) 2(0.1) 1.992 (0.365, 10.887) 0.4263 Any red blood cell transfusion 25(0.9)  15 (0.6)  1.665 (0.876, 3.166) 0.1197 Drop in hemoglobin and/orhematocrit 33 (1.2)  35 (1.3)  0.938 (0.581, 1.514) 0.7927 Bleed scoringcriteria ACUITY criteria Minor bleeding 320 (12.0)  246 (9.3)  1.335(1.120, 1.592) 0.0013 Major bleeding 147 (5.5)  93 (3.5)  1.607 (1.232,2.096) 0.0005 GUSTO criteria Mild bleeding 427 (16.0)  310 (11.7)  1.442(1.232, 1.688) <.0001 Moderate bleeding 20 (0.8)  13 (0.5)  1.536(0.762, 3.093) 0.2300 Severe/life-threatening bleeding 9 (0.3) 6 (0.2)1.495 (0.531, 4.205) 0.4462 TIMI criteria Minor bleeding 22 (0.8)  16(0.6)  1.372 (0.719, 2.618) 0.3376 Major bleeding 4 (0.2) 9 (0.3) 0.442(0.136, 1.436) 0.1742 Variables are presented as no. (%) unlessotherwise indicated. The bleeding options under each criterion are notmutually exclusive. For example, a patient may have a clinicallysignificant bleed and a minor bleed based on the ACUITY criteria, ifmore than 1 bleed is present. Each patient was counted only once foreach criteria level, regardless of the number of bleeds identified undereach criterion. Bleeding listed here included CABG-related bleeding.

The difference in ACUITY major bleeding was due to an excess of groinhematomas, but not more serious forms of bleeding. The rates of redblood cell transfusion were not significantly different (0.9% withcangrelor vs 0.6% with placebo; P=0.12). Notably, patients at higherrisk of bleeding, such as the elderly or those with prior stroke ortransient ischemic attack, did not have a higher rate of transfusionwith cangrelor (FIG. 4). There was no difference in the rate ofarrhythmia (2.3% vs 2.4%; P=0.7664) and the incidence of dyspnea washigher with cangrelor (1.4% [37] vs 0.5% [14]; P=0.0019).

The results demonstrate that important prespecified endpoints, includingstent thrombosis and mortality, were significantly reduced by cangrelor.

Example 2 Platelet Inhibition with Cangrelor in Patients with AcuteCoronary Syndromes Undergoing Percutaneous Coronary Intervention

In this example, the efficacy of cangrelor versus clopidogrel wasexamined when administered to patients before percutaneous coronaryintervention (PCI).

Patients were eligible for enrollment if they had stable angina,unstable angina, or non-ST-segment elevation (NSTE) MI with obstructivecoronary artery disease and were scheduled to undergo PCI. An additional1000 patients with STEMI for whom primary PCI was planned were alsoeligible. A protocol amendment issued in May 2007 required that patientshave definite features of an acute coronary syndrome (either STEMIundergoing planned primary PCI or a NSTE acute coronary syndrome withpositive cardiac biomarkers or chest pain with dynamicelectrocardiographic changes in patients ≧65 years or with diabetes).Patients could not have received fibrinolysis or glycoprotein IIb/IIIainhibitors within the prior 12 hours or clopidogrel >75 mg/day in theprior 5 days.

Patients were randomized in a 1:1 double-blind, double-dummy fashionusing an IVRS system to either cangrelor or clopidogrel. All patientsreceived a 30 μg/kg intravenous bolus of cangrelor or placebo followedby a 4 μg/kg/min intravenous infusion (FIG. 5). The infusion beganwithin 30 minutes prior to PCI and continued for at least 2 hours oruntil the conclusion of the index procedure, whichever was longer. Atthe treating physician's discretion, the infusion could be continued for4 hours. Patients received 600 mg encapsulated clopidogrel (four 150 mgcapsules) or placebo at the time of infusion. To allow the transitionfrom intravenous cangrelor to oral clopidogrel, patients ingestedanother four capsules (clopidogrel for cangrelor patients, placebo forclopidogrel patients) at the cessation of study drug infusion. Theduration of daily clopidogrel following the procedure was left to thediscretion of the treating physician, though additional clopidogrelbeyond the prescribed study medication was not allowed until the dayfollowing the index procedure.

All patients received aspirin 75-325 mg per local site standards.Adjunctive anticoagulants (unfractionated heparin, low molecular weightheparin, bivalirudin, or fondaparinux) and the procedural use ofglycoprotein IIb/IIIa inhibitors were determined by the treatingphysician.

The primary efficacy endpoint was the 48-hour composite of all-causemortality, MI, or ischemia-driven revascularization. Prespecifiedsecondary efficacy endpoints included the composite of mortality or MIat 48 hours and 30 days; the composite of mortality, MI, orischemia-driven revascularization at 30 days; the components of thecomposite endpoints at 48 hours and 30 days; stroke at 48 hours; abruptclosure, threatened abrupt closure, need for urgent coronary arterybypass grafting, or unsuccessful procedure during the index PCI; acute(24 hours) and subacute (48 hours) stent thrombosis; and all-causemortality at 6 months and 1 year.

Rates of MI and ischemia-driven revascularization up to 30 daysfollowing the index procedure were assessed. Ischemia-drivenrevascularization was defined as symptoms of myocardial ischemia leadingto urgent (within 24 hours of the last episode of ischemia)revascularization, which must have occurred after the index procedureconcluded (ie, guidewire removal). New electrocardiographic changes,acute pulmonary edema, ventricular arrhythmias, or hemodynamicinstability could also constitute evidence of ischemia.

MI was defined by a new Q wave (duration >0.03 seconds) in twocontiguous electrocardiographic leads or elevations in creatine kinase(CK) and CK-MB, including a rise of CK-MB ≧3 times the local upper limitor normal and, when biomarkers were elevated prior to PCI, an additional50% above baseline (Thygesen K. et al, Circulation 116:2634-53 (2007)).One baseline troponin measurement was required for patients undergoingurgent PCI. Measurements of CK-MB were obtained at 2, 10, 17, and 24hours post-PCI. Stent thrombosis was defined using Academic ResearchConsortium criteria (Cutlip D. E. et al., Circulation 115:2344-51(2007)).

Bleeding was assessed up to 48 hours using clinical and laboratorydefinitions. Multiple definitions of bleeding were used for fulldisclosure of bleeding risks associated with cangrelor: (1) The GlobalUtilization of Streptokinase and Tissue Plasminogen Activator forOccluded Coronary Arteries (GUSTO) criteria (The GUSTO Investigators. NEngl J Med 329:673-82 (1993); mild, moderate, or severe/life-threateningbased on transfusion use and presence/absence of hemodynamiccompromise); (2) Thrombolysis in Myocardial Infarction (TIMI) criteria(Chesebro J. H. et al., Circulation 76:142-54 (1987); minor or majorbleeding based on clinical and laboratory findings); (3) AcuteCatheterization and Urgent Intervention Triage Strategy (ACUITY)criteria (Stone G. W. et al., N Engl J Med 355:2203-16 (2006); usingdetailed clinical assessment, changes in hemoglobin, hematomas >5 cm,and need for blood transfusion). Investigators reported adverse andserious adverse events according to International Conference onHarmonization guidance (International Conference on Harmonization (ICH)Guidance Documents. U.S. Food and Drug Administration Web site.(Accessed on Oct. 8, 2009, at the FDA website beginning with “www.” andending with “fda.gov/RegulatoryInformation/Guidances/ucm122049.htm”)).

An independent clinical events committee reviewed and adjudicatedsuspected MI, ischemia-driven revascularization, stent thrombosis, andstroke blinded to knowledge of the study medication (Mahaffey K. W. etal., Am Heart J 143:242-8 (2002)).

Determination of periprocedural MI can be challenging when most patientshave elevated biomarkers and a single baseline sample. After the initialanalyses were completed and reviewed, additional post-hoc compositeswere performed to better understand the potential effect of the drug onperiprocedural outcomes less reliant on biomarkers (e.g., mortality,stent thrombosis, and Q-wave MI).

The sample size was based on the estimated composite incidence ofall-cause mortality, MI, and ischemia-driven revascularization at 48hours. Since there was no prior information about the use of cangrelorin the setting of STEMI and primary PCI and given the challenge ofmeasuring re-infarction in the early hours of STEMI, the primaryefficacy endpoint excluded these patients from the analysis, though theywere included in analyses of safety. The composite event rate wasestimated at 7% in the control clopidogrel arm. The trial was designedas a superiority trial to demonstrate a benefit of cangrelor over 600 mgclopidogrel. Assuming a 22% risk reduction, a sample size of 8000patients would provide approximately 82% power with an alpha level of0.05. The plan was to include up to 1000 patients with STEMI, raisingthe sample size to 9000 patients.

The primary efficacy analysis was to be determined in the modifiedintent-to-treat (mITT) population, defined as all randomized patients(excluding STEMI cohort) who received at least one dose of study drugand underwent the index PCI. The safety population consisted of allrandomized patients who received any study drug. Patients in the safetyanalyses were assigned to a treatment arm based on treatment received,not as randomized. The ITT analysis with and without the STEMI cohort isreported.

All statistical tests were two-tailed using a level of significance of0.05. The primary endpoint comparison between the cangrelor and placeboarms was performed by calculating an odds ratio (OR), with accompanying95% confidence intervals (CI), using logistic regression. Logisticregression was used to analyze the majority of the remaining secondaryendpoints. Continuous variables are summarized by medians andinterquartile ranges. Categorical variables are summarized byfrequencies and percentages. In the secondary efficacy analyses, therewas no attempt to adjust the P values for the multiplicity issue. Theseanalyses were considered exploratory and hypothesis-generating.

At the end of the study, 98% (n=8877) of the expected 9000 patients hadbeen enrolled at 268 sites across 14 countries. For the 48-hour and30-day endpoints, vital status follow-up was 99.7% and 98.6% complete,respectively.

Baseline demographics on the ITT population are shown in Table 5.Baseline demographics for the MITT and safety populations are shown inTables 6 and 7.

TABLE 5 Baseline characteristics for ITT Population ITT ITT WithoutSTEMI Cangrelor Clopidogrel Cangrelor Clopidogrel Baselinecharacteristics (N = 4433) (N = 4444) (N = 3946) (N = 3935) Age, yrs62.0 (54.0, 70.0) 62.0 (54.0, 71.0) 63.0 (55.0, 71.0) 62.0 (54.0, 71.0)Sex, No. (%) Male 3275 (73.9) 3209 (72.2) 2891 (73.3) 2831 (71.9) Female1158 (26.1) 1235 (27.8) 1055 (26.7) 1104 (28.1) Race, No. (%) White 3658(82.6) 3626 (81.7) 3229 (81.9) 3184 (81.0) Asian 311 (7.0) 313 (7.1) 294(7.5) 300 (7.6) Black 215 (4.9) 239 (5.4) 190 (4.8) 208 (5.3) Hispanic209 (4.7) 218 (4.9) 197 (5.0) 204 (5.2) Other 35 (0.8) 42 (1.0) 31 (0.8)34 (0.9) Weight, kg 84.0 (73.0, 97.0) 84.0 (73.0, 97.0) 84.0 (73.0,97.0) 84.0 (73.0, 98.0) Height, cm 172.0 (165.0, 178.0) 172.0 (165.0,178.0) 172.0 (165.0, 178.0) 172.0 (165.0, 178.0) Stable angina, No. (%)668 (15.1) 665 (15.0) 668 (16.9) 665 (16.9) Unstable angina, No. (%)1097 (24.7) 1088 (24.5) 1097 (27.8) 1088 (27.6) Urgent NSTEMI, No. (%)639 (14.4) 640 (14.4) 639 (16.2) 640 (16.3) NSTEMI, No. (%) 1542 (34.8)1542 (34.7) 1542 (39.1) 1542 (39.2) STEMI, No. (%) 487 (11.0) 509 (11.5)0 (0.0) 0 (0.0) Medical history, No. (%) Diabetes mellitus 1350 (30.5)1352 (30.5) 1248 (31.6) 1263 (32.1) Current smoker 1247 (28.5) 1283(29.1) 1035 (26.6) 1076 (27.6) Hypertension 3181 (72.1) 3139 (71.0) 2900(73.8) 2839 (72.4) Hyperlipidemia 2825 (66.6) 2777 (65.5) 2590 (68.4)2536 (67.4) Stroke/TIA 223 (5.1) 227 (5.1) 208 (5.3) 205 (5.2) Familyhistory of CAD 1843 (45.9) 1873 (46.5) 1656 (46.1) 1686 (47.1) MI 1075(24.6) 1089 (24.8) 1003 (25.9) 1007 (26.0) PTCA/PCI 1266 (28.6) 1261(28.5) 1193 (30.3) 1198 (30.6) CABG 557 (12.6) 552 (12.4) 541 (13.7) 532(13.5) Congestive HF 333 (7.6) 338 (7.7) 319 (8.2) 322 (8.3) PAD 323(7.4) 315 (7.2) 294 (7.6) 290 (7.5) Periprocedural medications, No. (%)Bivalirudin 1313 (29.6) 1337 (30.1) 1244 (31.5) 1250 (31.8) UFH 2437(55.0) 2452 (55.3) 2154 (54.6) 2155 (54.8) LMWH 368 (8.3) 340 (7.7) 322(8.2) 298 (7.6) GP IIb/IIIa 1163 (26.3) 1183 (26.7) 909 (23.0) 927(23.6) Study treatment Number of target vessels, No. (%) 1 3836 (88.0)3796 (87.4) 3406 (87.3) 3360 (86.5) 2 484 (11.1) 509 (11.7) 457 (11.7)488 (12.6) 3 38 (0.9) 36 (0.8) 38 (1.0) 35 (0.9) Drug-eluting stent,2581 (59.2) 2560 (59.0) 2422 (62.1) 2383 (61.4) No. (%) Non-drug-elutingstent, 1640 (37.6) 1635 (37.7) 1367 (35.0) 1380 (35.5) No. (%)Angiographic complications (site reported) Threatened abrupt 13 (0.3) 12(0.3) 9 (0.2) 10 (0.3) closure Unsuccessful procedure 90 (2.1) 103 (2.4)81 (2.1) 92 (2.4) Abrupt vessel closure 24 (0.6) 22 (0.5) 20 (0.5) 19(0.5) New thrombus or 17 (0.4) 23 (0.5) 16 (0.4) 16 (0.4) suspectedthrombus Acute stent thrombosis 2 (0.0) 5 (0.1) 2 (0.1) 5 (0.1) Need forurgent CABG 10 (0.2) 7 (0.2) 8 (0.2) 7 (0.2) IV study drug administered,4367 (98.5) 4355 (98.0) 3904 (99.0) 3883 (98.7) No. (%) Bolusadministered, No. (%) 4367 (98.5) 4354 (98.0) 3904 (99.0) 3883 (98.7)Infusion administered, 4364 (98.5) 4353 (98.0) 3901 (98.9) 3882 (98.7)No. (%) Duration of infusion, hrs 2.1 (2.0, 2.2) 2.1 (2.0, 2.2) 2.1(2.0, 2.2) 2.1 (2.0, 2.2) Oral study drug 4351 (98.2) 4345 (97.8) 3896(98.8) 3882 (98.7) administered, No. (%) ITT With STEMI CangrelorClopidogrel Baseline characteristics (N = 487) (N = 509) Age, yrs 58.0(51.0, 67.0) 61.0 (52.0, 70.0) Sex, No. (%) Male 384 (78.9) 378 (74.3)Female 103 (21.1) 131 (25.7) Race, No. (%) White 429 (88.1) 442 (87.0)Asian 17 (3.5) 13 (2.6) Black 25 (5.1) 31 (6.1) Hispanic 12 (2.5) 14(2.8) Other 4 (0.8) 8 (1.6) Weight, kg 83 (72.0, 95.0) 82.0 (72.0, 95.0)Height, cm 173.0 (167.6, 178.0) 172.0 (165.0, 178.0) Stable angina, No.(%) 0 (0.0) 0 (0.0) Unstable angina, No. (%) 0 (0.0) 0 (0.0) UrgentNSTEMI, No. (%) 0 (0.0) 0 (0.0) NSTEMI, No. (%) 0 (0.0) 0 (0.0) STEMI,No. (%) 487 (100.0) 509 (100.0) Medical history, No. (%) Diabetesmellitus 102 (20.9) 89 (17.5) Current smoker 212 (43.7) 207 (41.2)Hypertension 281 (58.1) 300 (60.0) Hyperlipidemia 235 (51.5) 241 (50.8)Stroke/TIA 15 (3.1) 22 (4.4) Family history of CAD 187 (43.7) 187 (41.6)MI 72 (14.9) 82 (16.2) PTCA/PCI 73 (15.0) 63 (12.4) CABG 16 (3.3) 20(3.9) Congestive HF 14 (2.9) 16 (3.2) PAD 29 (6.0) 25 (5.0)Periprocedural medications, No. (%) Bivalirudin 69 (14.2) 87 (17.1) UFH283 (58.2) 297 (58.5) LMWH 46 (9.5) 42 (8.3) GP IIb/IIIa 254 (52.3) 256(50.4) Study treatment Number of target vessels, No. (%) 1 430 (94.1)436 (95.2) 2 27 (5.9) 21 (4.6) 3 0 (0.0) 1 (0.2) Drug-eluting stent, 159(34.8) 177 (38.6) No. (%) Non-drug-eluting stent, 273 (59.7) 255 (55.7)No. (%) Angiographic complications (site reported) Threatened abrupt 4(0.9) 2 (0.4) closure Unsuccessful procedure 9 (2.0) 11 (2.4) Abruptvessel closure 4 (0.9) 3 (0.7) New thrombus or 1 (0.2) 7 (1.5) suspectedthrombus Acute stent thrombosis 0 (0.0) 0 (0.0) Need for urgent CABG 2(0.4) 0 (0.0) IV study drug administered, 463 (95.1) 472 (92.7) No. (%)Bolus administered, No. (%) 463 (95.1) 471 (92.5) Infusion administered,463 (95.1) 471 (92.5) No. (%) Duration of infusion, hrs 2.0 (2.0, 2.2)2.1 (2.0, 2.2) Oral study drug 455 (93.4) 463 (91.0) administered, No.(%) Variables are presented as median (25th, 75th) unless otherwiseindicated. CABG denotes coronary artery bypass grafting; CAD, coronaryartery disease; GP, glycoprotein; HF, heart failure; ITT, intent totreat; IV, intravenous; LMWH, low molecular weight heparin; MI,myocardial infarction; NSTEMI, non-ST-segment elevation myocardialinfarction; PAD, peripheral artery disease; PCI, percutaneous coronaryintervention; PTCA, percutaneous transluminal coronary angioplasty;STEMI, ST-segment elevation myocardial infarction; TIA, transientischemic attack; UFH, unfractionated heparin.

TABLE 6 MITT and MITT NSTEMI Population MITT MITT NSTEMI CangrelorClopidogrel Cangrelor Clopidogrel Baseline characteristics (N = 4347) (N= 4320) (N = 3897) (N = 3871) Age, yrs 62.0 (54.0, 70.0) 62.0 (54.0,71.0) 63.0 (55.0, 70.0) 62.0 (54.0, 71.0) Sex, No. (%) Male 3212 (73.9)3124 (72.3) 2854 (73.2) 2786 (72.0) Female 1135 (26.1) 1196 (27.7) 1043(26.8) 1085 (28.0) Race, No. (%) White 3589 (82.7) 3516 (81.5) 3193(82.0) 3127 (80.9) Asian 306 (7.0) 312 (7.2) 289 (7.4) 299 (7.7) Black208 (4.8) 230 (5.3) 185 (4.8) 205 (5.3) Hispanic 205 (4.7) 214 (5.0) 194(5.0) 201 (5.2) Other 34 (0.8) 42 (1.0) 31 (0.8) 34 (0.9) Weight, kg84.0 (73.0, 97.0) 84.0 (73.0, 97.0) 84.0 (73.0, 97.0) 84.0 (73.0, 97.0)Height, cm 172.0 (165.0, 178.0) 172.0 (165.0, 178.0) 172.0 (165.0,178.0) 172.0 (165.0, 178.0) Stable angina, No. (%) 659 (15.2) 645 (14.9)659 (16.9) 645 (16.7) Unstable angina, No. (%) 1088 (25.0) 1071 (24.8)1088 (27.9) 1071 (27.7) Urgent NSTEMI, No. (%) 627 (14.4) 632 (14.6) 627(16.1) 632 (16.3) NSTEMI, No. (%) 1523 (35.0) 1523 (35.3) 1523 (39.1)1523 (39.3) STEMI, No. (%) 450 (10.4) 449 (10.4) 0 (0.0) 0 (0.0) Medicalhistory, No. (%) Diabetes mellitus 1327 (30.5) 1313 (30.4) 1233 (31.7)1238 (32.0) Current smoker 1229 (28.6) 1245 (29.0) 1025 (26.6) 1057(27.5) Hypertension 3122 (72.2) 3045 (70.9) 2865 (73.8) 2788 (72.3)Hyperlipidemia 2771 (66.6) 2705 (65.7) 2555 (68.3) 2491 (67.3)Stroke/TIA 220 (5.1) 218 (5.1) 206 (5.3) 201 (5.2) Family history of CAD1809 (45.9) 1825 (46.6) 1637 (46.1) 1656 (47.1) MI 1059 (24.7) 1054(24.7) 991 (25.9) 983 (25.8) PTCA/PCI 1247 (28.8) 1229 (28.6) 1181(30.4) 1172 (30.4) CABG 546 (12.6) 537 (12.4) 533 (13.7) 521 (13.5)Congestive HF 325 (7.5) 326 (7.6) 314 (8.1) 311 (8.1) PAD 320 (7.5) 304(7.2) 292 (7.6) 282 (7.4) Periprocedural medications, No. (%)Bivalirudin 1298 (29.9) 1316 (30.5) 1232 (31.6) 1232 (31.8) UFH 2399(55.2) 2404 (55.7) 2134 (54.8) 2132 (55.1) LMWH 364 (8.4) 334 (7.7) 319(8.2) 297 (7.7) GP IIb/IIIa 1148 (26.4) 1160 (26.9) 903 (23.2) 921(23.8) Study treatment Number of target vessels, No. (%) 1 3818 (88.0)3772 (87.4) 3395 (87.3) 3345 (86.5) 2 482 (11.1) 506 (11.7) 455 (11.7)485 (12.5) 3 38 (0.9) 36 (0.8) 38 (1.0) 35 (0.9) Drug-eluting stent, No.(%) 2572 (59.3) 2547 (59.0) 2415 (62.1) 2375 (61.4) Non-drug-elutingstent, No. 1632 (37.6) 1628 (37.7) 1362 (35.0) 1375 (35.6) (%)Angiographic complications (site reported) Threatened abrupt closure 13(0.3) 12 (0.3) 9 (0.2) 10 (0.3) Unsuccessful procedure 90 (2.1) 103(2.4) 81 (2.1) 92 (2.4) Abrupt vessel closure 24 (0.6) 22 (0.5) 20 (0.5)19 (0.5) New thrombus or suspected 17 (0.4) 22 (0.5) 16 (0.4) 16 (0.4)thrombus Acute stent thrombosis 2 (0.0) 5 (0.1) 2 (0.1) 5 (0.1) Need forurgent CABG 8 (0.2) 6 (0.1) 7 (0.2) 6 (0.2) IV study drug administered,No. 4345 (100.0) 4317 (99.9) 3895 (99.9) 3868 (99.9) (%) Bolusadministered, No. (%) 4345 (100.0) 4316 (99.9) 3895 (99.9) 3868 (99.9)Infusion administered, No. (%) 4344 (99.9) 4317 (99.9) 3894 (99.9) 3868(99.9) Duration of infusion, hrs 2.1 (2.0, 2.2) 2.1 (2.0, 2.2) 2.1 (2.0,2.2) 2.1 (2.0, 2.2) Oral study drug administered, No. 4329 (99.6) 4305(99.7) 3884 (99.7) 3863 (99.8) (%) Variables are presented as median(25th, 75th) unless otherwise indicated. CABG denotes coronary arterybypass grafting; CAD, coronary artery disease; GP, glycoprotein; HF,heart failure; IV, intravenous; LMWH, low molecular weight heparin; MI,myocardial infarction; MITT, modified intent to treat; NSTEMI,non-ST-segment elevation myocardial infarction; PAD, peripheral arterydisease; PCI, percutaneous coronary intervention; PTCA, percutaneoustransluminal coronary angioplasty; STEMI, ST-segment elevationmyocardial infarction; TIA, transient ischemic attack; UFH,unfractionated heparin.

TABLE 7 Safety Population Cangrelor Clopidogrel Baseline characteristics(N = 4374) (N = 4365) Age, yrs 62.0 (54.0, 70.0) 62.0 (54.0, 71.0) Sex,No. (%) Male 3229 (73.8) 3149 (72.1) Female 1145 (26.2) 1216 (27.9)Race, No. (%) White 3610 (82.6) 3558 (81.6) Asian 309 (7.1) 312 (7.2)Black 208 (4.8) 233 (5.3) Hispanic 206 (4.7) 215 (4.9) Other 36 (0.8) 41(1.0) Weight, kg 84.0 (73.0, 97.0) 84.0 (73.0, 97.0) Height, cm 172.0(165.0, 178.0) 172.0 (165.0, 178.0) Stable angina, No. (%) 661 (15.1)654 (15.0) Unstable angina, No. (%) 1091 (24.9) 1074 (24.6) UrgentNSTEMI, 629 (14.4) 634 (14.5) No. (%) NSTEMI, No. (%) 1529 (35.0) 1529(35.0) STEMI, No. (%) 463 (10.6) 475 (10.9) Medical history, No. (%)Diabetes mellitus 1337 (30.6) 1325 (30.4) Current smoker 1233 (28.5)1257 (29.0) Hypertension 3143 (72.2) 3083 (71.0) Hyperlipidemia 2787(66.6) 2728 (65.6) Stroke/TIA 220 (5.1) 221 (5.1) Family history of CAD1818 (45.8) 1838 (46.5) MI 1064 (24.7) 1067 (24.8) PTCA/PCI 1253 (28.7)1237 (28.4) CABG 550 (12.6) 540 (12.4) Congestive HF 328 (7.6) 332 (7.7)PAD 321 (7.5) 309 (7.2) Periprocedural medications, No. (%) Bivalirudin1299 (29.7) 1320 (30.2) UFH 2413 (55.2) 2424 (55.5) LMWH 365 (8.4) 340(7.8) GP IIb/IIIa 1154 (26.4) 1170 (26.8) Study treatment Number oftarget vessels, No. (%) 1 3819 (88.0) 3771 (87.4) 2 482 (11.1) 506(11.7) 3 38 (0.9) 36 (0.8) Drug-eluting stent, 2572 (59.3) 2547 (59.0)No. (%) Non-drug-eluting 1633 (37.6) 1627 (37.7) stent, No. (%)Angiographic complications (site reported) Threatened abrupt 13 (0.3) 12(0.3) closure Unsuccessful procedure 90 (2.1) 103 (2.4) Abrupt vesselclosure 24 (0.6) 22 (0.5) New thrombus or 17 (0.4) 22 (0.5) suspectedthrombus Acute stent thrombosis 2 (0.0) 5 (0.1) Need for urgent CABG 8(0.2) 6 (0.1) IV study drug 4368 (99.9) 4354 (99.7) administered, No.(%) Bolus administered, 4368 (99.9) 4353 (99.7) No. (%) Infusionadministered, 4365 (99.8) 4352 (99.7) No. (%) Duration of infusion, hrs2.1 (2.0, 2.2) 2.1 (2.0, 2.2) Oral study drug 4352 (99.5) 4344 (99.5)administered, No. (%) Variables are presented as median (25th, 75th)unless otherwise indicated. CABG denotes coronary artery bypassgrafting; CAD, coronary artery disease; GP, glycoprotein; HF, heartfailure; IV, intravenous; LMWH, low molecular weight heparin; MI,myocardial infarction; NSTEMI, non-ST-segment elevation myocardialinfarction; PAD, peripheral artery disease; PCI, percutaneous coronaryintervention; PTCA, percutaneous transluminal coronary angioplasty;STEMI, ST-segment elevation myocardial infarction; TIA, transientischemic attack; UFH, unfractionated heparin.

There were no significant differences regarding baselinecharacteristics. Enrolled patients were typical of a contemporary PCIpopulation, being mostly men and having a median age of 62 years (54.0,71.0). Diabetes was noted in 30.5% while hypertension or hyperlipidemiawas present in the majority of patients. Previous cardiac eventsincluded MI in 24.7% and revascularization in 41.1% (28.6% PCI, 12.5%bypass grafting). Almost half (49%) of enrolled patients had NSTEMI atbaseline while stable angina and unstable angina were the baselinediagnoses in 15.0% and 24.6%, respectively. The STEMI cohort included996 (11.2%) patients.

During the index procedure, a majority of patients (55.1%) receivedunfractionated heparin, and 29.9% received bivalirudin. GlycoproteinIIb/IIIa inhibitors were used in 26.5% with most receiving eptifibatide(75.0%). Almost all (98%) patients in the ITT population received studydrug. Sites were instructed to start PCI within 30 minutes ofclopidogrel capsules.

PCI was attempted in all but 161 patients (1.8%), 65 in the cangrelorgroup (1.5%) and 96 in the clopidogrel group (2.2%). The median durationof PCI was 0.4 hours (0.2, 0.6) and the median time from hospitaladmission to PCI was 6.3 hours (2.6, 23.7). Most procedures involvedsingle-vessel or two-vessel PCI (87.7% and 11.4%, respectively).Drug-eluting stents were used in the majority of interventions (59.1%),bare-metal stents were used in 37.6%.

Cangrelor was equivalent to 600 mg clopidogrel in the primary compositeof all-cause mortality, MI, or ischemia-driven revascularization at 48hours (7.5% vs 7.1%; OR 1.05, 95% CI 0.88, 1.24; P=0.59) (Table 8).

TABLE 8 48-hour endpoints for MITT Without STEMI Population MITT WithoutSTEMI Cangrelor Clopidogrel (N = 3897) (N = 3871) OR (95% CI) P ValueAdjudicated endpoints Mortality/MI/IDR (primary 290 (7.5) 276 (7.1) 1.05(0.88, 1.24) 0.59 endpoint) MI 278 (7.1) 256 (6.6) 1.09 (0.91, 1.29)0.36 IDR 13 (0.3) 23 (0.6) 0.56 (0.28, 1.11) 0.10 All-cause mortality 8(0.2) 5 (0.1) 1.59 (0.52, 4.87) 0.42 Stent thrombosis 7 (0.2) 11 (0.3)0.63 (0.25, 1.63) 0.34 Stroke 6 (0.2) 7 (0.2) 0.85 (0.29, 2.54) 0.77Q-wave MI 4 (0.1) 10 (0.3) 0.40 (0.12, 1.27) 0.12 Exploratory endpointsMortality/Q-wave MI/IDR 23 (0.6) 34 (0.9) 0.67 (0.39, 1.14) 0.14Mortality/Q-wave MI/Stent 18 (0.5) 23 (0.6) 0.78 (0.42, 1.44) 0.42thrombosis

The primary efficacy composite did not differ at 30 days (Table 9).FIGS. 6A and 6B display the primary endpoint OR data for key subgroups.

TABLE 9 30-day endpoints for ITT, MITT, and Safety Populations ITTCangrelor Clopidogrel (N = 4433) (N = 4444) OR (95% CI) P ValueMortality/MI/IDR 381 (8.7) 373 (8.5) 1.026 (0.884, 1.192) 0.7332 MI 318(7.3) 293 (6.7) 1.095 (0.929, 1.291) 0.2799 IDR 62 (1.4) 69 (1.6) 0.899(0.637, 1.271) 0.5475 All-cause mortality 40 (0.9) 47 (1.1) 0.852(0.558, 1.301) 0.4583 Stent thrombosis 27 (0.6) 30 (0.7) 0.902 (0.535,1.519) 0.6973 Q-wave MI 9 (0.2) 15 (0.3) 0.601 (0.263, 1.374) 0.2273Mortality/Q-wave 102 (2.3) 119 (2.7) 0.856 (0.655, 1.119) 0.2550 MI/IDRMortality/Q-wave 68 (1.6) 82 (1.9) 0.829 (0.599, 1.146) 0.2560 MI/Stentthrombosis ITT Without STEMI Cangrelor Clopidogrel (N = 3946) (N = 3935)OR (95% CI) P Value Mortality/MI/IDR 345 (8.8) 332 (8.6) 1.037 (0.886,1.215) 0.6481 MI 298 (7.6) 276 (7.1) 1.081 (0.912, 1.281) 0.3718 IDR 46(1.2) 54 (1.4) 0.846 (0.569, 1.257) 0.4072 All-cause mortality 32 (0.8)31 (0.8) 1.027 (0.626, 1.687) 0.9148 Stent thrombosis 20 (0.5) 20 (0.5)0.995 (0.535, 1.852) 0.9877 Q-wave MI 7 (0.2) 15 (0.4) 0.463 (0.189,1.138) 0.0933 Mortality/Q-wave 79 (2.0) 88 (2.3) 0.891 (0.656, 1.211)0.4620 MI/IDR Mortality/Q-wave 54 (1.4) 56 (1.4) 0.959 (0.658, 1.397)0.8276 MI/Stent thrombosis ITT With STEMI Cangrelor Clopidogrel (N =487) (N = 509) OR (95% CI) P Value Mortality/MI/IDR 36 (7.6) 41 (8.2)0.929 (0.582, 1.480) 0.7553 MI 20 (4.2) 17 (3.4) 1.263 (0.653, 2.441)0.4882 IDR 16 (3.4) 15 (3.0) 1.139 (0.557, 2.331) 0.7210 All-causemortality 8 (1.7) 16 (3.2) 0.524 (0.222, 1.235) 0.1397 Stent thrombosis7 (1.5) 10 (2.0) 0.741 (0.280, 1.962) 0.5460 Q-wave MI 2 (0.4) 0 (0.0) —— Mortality/Q-wave 23 (4.9) 31 (6.2) 0.778 (0.447, 1.355) 0.3760 MI/IDRMortality/Q-wave 14 (3.0) 26 (5.2) 0.560 (0.289, 1.085) 0.0859 MI/Stentthrombosis MITT Cangrelor Clopidogrel (N = 4347) (N = 4320) OR (95% CI)P Value Mortality/MI/IDR 376 (8.7) 360 (8.4) 1.042 (0.895, 1.211) 0.5979MI 315 (7.3) 292 (6.8) 1.078 (0.914, 1.271) 0.3747 IDR 60 (1.4) 66 (1.5)0.902 (0.634, 1.283) 0.5660 All-cause mortality 40 (0.9) 38 (0.9) 1.046(0.670, 1.635) 0.8419 Stent thrombosis 27 (0.6) 30 (0.7) 0.894 (0.530,1.506) 0.6728 Q-wave MI 9 (0.2) 15 (0.4) 0.595 (0.260, 1.362) 0.2194Mortality/Q-wave 100 (2.3) 107 (2.5) 0.927 (0.703, 1.222) 0.5904 MI/IDRMortality/Q-wave 68 (1.6) 73 (1.7) 0.924 (0.663, 1.290) 0.6439 MI/Stentthrombosis MITT Without STEMI Cangrelor Clopidogrel (N = 3897) (N =3871) OR (95% CI) P Value Mortality/MI/IDR 342 (8.9) 326 (8.5) 1.044(0.891, 1.224) 0.5950 MI 297 (7.7) 276 (7.2) 1.072 (0.905, 1.272) 0.4208IDR 44 (1.1) 52 (1.4) 0.837 (0.559, 1.254) 0.3882 All-cause mortality 32(0.8) 27 (0.7) 1.177 (0.704, 1.967) 0.5355 Stent thrombosis 20 (0.5) 20(0.5) 0.991 (0.533, 1.846) 0.9783 Q-wave MI 7 (0.2) 15 (0.4) 0.462(0.188, 1.134) 0.0917 Mortality/Q-wave 77 (2.0) 82 (2.1) 0.930 (0.679,1.273) 0.6489 MI/IDR Mortality/Q-wave 54 (1.4) 52 (1.4) 1.030 (0.702,1.511) 0.8799 MI/Stent thrombosis MITT With STEMI Cangrelor Clopidogrel(N = 450) (N = 449) OR (95% CI) P Value Mortality/MI/IDR 34 (7.8) 34(7.7) 1.015 (0.619, 1.665) 0.9534 MI 18 (4.1) 16 (3.6) 1.146 (0.577,2.278) 0.6965 IDR 16 (3.7) 14 (3.2) 1.165 (0.561, 2.416) 0.6825All-cause mortality 8 (1.8) 11 (2.5) 0.732 (0.292, 1.838) 0.5072 Stentthrombosis 7 (1.6) 10 (2.3) 0.705 (0.266, 1.869) 0.4821 Q-wave MI 2(0.5) 0 (0.0) — — Mortality/Q-wave 23 (5.3) 25 (5.6) 0.929 (0.519,1.663) 0.8039 MI/IDR Mortality/Q-wave 14 (3.2) 21 (4.7) 0.665 (0.334,1.325) 0.2464 MI/Stent thrombosis Safety Cangrelor Clopidogrel (N =4374) (N = 4365) OR (95% CI) P Value Mortality/MI/IDR 379 (8.8) 365(8.5) 1.040 (0.895, 1.209) 0.6074 MI 318 (7.4) 293 (6.8) 1.090 (0.925,1.285) 0.3039 IDR 60 (1.4) 67 (1.6) 0.893 (0.628, 1.268) 0.5257All-cause mortality 40 (0.9) 41 (0.9) 0.974 (0.629, 1.508) 0.9053 Stentthrombosis 27 (0.6) 30 (0.7) 0.898 (0.533, 1.513) 0.6858 Q-wave MI 9(0.2) 15 (0.3) 0.598 (0.262, 1.368) 0.2236 Mortality/Q-wave 100 (2.3)111 (2.6) 0.897 (0.682, 1.179) 0.4364 MI/IDR Mortality/Q-wave 68 (1.6)76 (1.8) 0.892 (0.641, 1.240) 0.4954 MI/Stent thrombosis Variables arepresented as no. (%) unless otherwise indicated. CI denotes confidenceinterval; IDR, ischemia-driven revascularization; ITT, intent to treat;MI, myocardial infarction; MITT, modified intent to treat; OR, oddsratio; STEMI, ST-segment elevation myocardial infarction.

Forty-eight-hour bleeding events as observed in the safety population(including those with STEMI) are in Table 10. Reported adverse eventswere comparable between the groups (26.4% cangrelor, 25.7% clopidogrel)and discontinuation of study drug due to an adverse event was unusual inboth groups (0.5% in both). Serious adverse events were infrequent andsimilar between the groups (2.7% in both). Dyspnea was reported in 1.0%of cangrelor patients compared with 0.4% of clopidogrel patients(P=0.001).

TABLE 10 48-hour bleeding events for safety population CangrelorClopidogrel Bleeding events (N = 4374) (N = 4365) OR (95% CI) P ValueAccess site bleeding requiring 6 (0.1) 10 (0.2) 0.60 (0.22, 1.65) 0.32radiologic or surgical intervention Hematoma ≧5 cm at puncture site 85(1.9) 76 (1.7) 1.12 (0.82, 1.53) 0.48 Intracranial hemorrhage 1 (0.0) 0(0.0) Intraocular 2 (0.0) 0 (0.0) Reoperation for bleeding 1 (0.0) 1(0.0) 1.00 (0.06, 15.96) 1.00 Retroperitoneal 15 (0.3) 10 (0.2) 1.50(0.67, 3.34) 0.32 Ecchymosis 284 (6.5) 234 (5.4) 1.23 (1.03, 1.47) 0.03Epistaxis 9 (0.2) 22 (0.5) 0.41 (0.19, 0.89) 0.02 Hematoma <5 cm atpuncture site 251 (5.7) 222 (5.1) 1.14 (0.94, 1.37) 0.18 Oozing atpuncture site 400 (9.1) 319 (7.3) 1.28 (1.10, 1.49) 0.002Thrombocytopenia 6 (0.1) 7 (0.2) 0.86 (0.29, 2.55) 0.78 Hemodynamiccompromise 9 (0.2) 11 (0.3) 0.82 (0.34, 1.97) 0.65 Any blood transfusion46 (1.1) 42 (1.0) 1.09 (0.72, 1.67) 0.68 Any platelet transfusion 6(0.1) 5 (0.1) 1.20 (0.37, 3.93) 0.77 Drop in hemoglobin and/orhematocrit 91 (2.1) 63 (1.4) 1.45 (1.05, 2.01) 0.02 Bleed scoringcriteria ACUITY criteria Minor bleeding 768 (17.6) 663 (15.2) 1.19(1.06, 1.33) 0.003 Major bleeding 158 (3.6) 126 (2.9) 1.26 (0.99, 1.60)0.06 GUSTO criteria Mild bleeding 858 (19.6) 739 (16.9) 1.20 (1.07,1.34) 0.001 Moderate bleeding 41 (0.9) 34 (0.8) 1.21 (0.76, 1.90) 0.42Severe/life-threatening bleeding 10 (0.2) 11 (0.3) 0.91 (0.39, 2.14)0.82 TIMI criteria Minor bleeding 36 (0.8) 26 (0.6) 1.39 (0.84, 2.30)0.21 Major bleeding 19 (0.4) 14 (0.3) 1.36 (0.68, 2.71) 0.39 Variablesare presented as no. (%) unless otherwise indicated. The bleedingoptions under each criterion are not mutually exclusive. For example, apatient may have a clinically significant bleed and a minor bleed basedon the ACUITY criteria, if more than 1 bleed is present. Each patientwill be counted once for each criteria level, regardless of the numberof bleeds identified under each criterion.

Key secondary and composite exploratory (post-hoc) endpoints aredisplayed in Table 11.

TABLE 11 48-hour endpoints for ITT, MITT, and Safety Populations MITTWithout STEMI Cangrelor Clopidogrel (N = 3897) (N = 3871) OR (95% CI) PValue Mortality/MI/IDR (Prespecified 290 (7.5) 276 (7.1) 1.048 (0.883,1.243) 0.5929 primary endpoint) MI 278 (7.1) 256 (6.6) 1.085 (0.910,1.294) 0.3616 IDR 13 (0.3) 23 (0.6) 0.560 (0.283, 1.108) 0.0957All-cause mortality 8 (0.2) 5 (0.1) 1.591 (0.520, 4.869) 0.4155 Stentthrombosis 7 (0.2) 11 (0.3) 0.632 (0.245, 1.631) 0.3427 Stroke 6 (0.2) 7(0.2) 0.852 (0.286, 2.536) 0.7730 Q-wave MI 4 (0.1) 10 (0.3) 0.397(0.124, 1.267) 0.1186 Mortality/Q-wave MI/IDR 23 (0.6) 34 (0.9) 0.670(0.394, 1.140) 0.1399 Mortality/Q-wave MI/Stent 18 (0.5) 23 (0.6) 0.777(0.419, 1.442) 0.4233 thrombosis ITT Cangrelor Clopidogrel (N = 4433) (N= 4444) OR (95% CI) P Value Mortality/MI/IDR 312 (7.1) 297 (6.7) 1.058(0.898, 1.248) 0.4990 MI 294 (6.7) 265 (6.0) 1.122 (0.945, 1.331) 0.1899IDR 21 (0.5) 31 (0.7) 0.678 (0.389, 1.182) 0.1710 All-cause mortality 9(0.2) 11 (0.2) 0.821 (0.340, 1.983) 0.6607 Stent thrombosis 11 (0.2) 15(0.3) 0.735 (0.337, 1.603) 0.4393 Stroke 6 (0.1) 8 (0.2) 0.752 (0.261,2.170) 0.5986 Q-wave MI 4 (0.1) 10 (0.2) 0.401 (0.126, 1.279) 0.1226Mortality/Q-wave MI/IDR 32 (0.7) 48 (1.1) 0.667 (0.425, 1.045) 0.0770Mortality/Q-wave MI/Stent 23 (0.5) 33 (0.7) 0.698 (0.409, 1.191) 0.1869thrombosis ITT Without STEMI Cangrelor Clopidogrel (N = 3946) (N = 3935)OR (95% CI) P Value Mortality/MI/IDR 292 (7.4) 277 (7.1) 1.056 (0.890,1.252) 0.5323 MI 278 (7.1) 256 (6.5) 1.090 (0.914, 1.299) 0.3378 IDR 15(0.4) 23 (0.6) 0.649 (0.338, 1.246) 0.1943 All-cause mortality 8 (0.2) 6(0.2) 1.331 (0.461, 3.839) 0.5969 Stent thrombosis 7 (0.2) 11 (0.3)0.634 (0.246, 1.638) 0.3469 Stroke 6 (0.2) 7 (0.2) 0.855 (0.287, 2.546)0.7784 Q-wave MI 4 (0.1) 10 (0.3) 0.398 (0.125, 1.272) 0.1202Mortality/Q-wave MI/IDR 25 (0.6) 35 (0.9) 0.711 (0.425, 1.190) 0.1941Mortality/Q-wave MI/Stent 18 (0.5) 24 (0.6) 0.747 (0.405, 1.379) 0.3511thrombosis ITT With STEMI Cangrelor Clopidogrel (N = 487) (N = 509) OR(95% CI) P Value Mortality/MI/IDR 20 (4.1) 20 (3.9) 1.054 (0.560, 1.985)0.8703 MI 16 (3.3) 9 (1.8) 1.900 (0.831, 4.341) 0.1280 IDR 6 (1.2) 8(1.6) 0.786 (0.271, 2.283) 0.6584 All-cause mortality 1 (0.2) 5 (1.0)0.209 (0.024, 1.793) 0.1534 Stent thrombosis 4 (0.8) 4 (0.8) 1.052(0.262, 4.321) 0.9428 Stroke 0 (0.0) 1 (0.2) — — Q-wave MI 0 (0.0) 0(0.0) — — Mortality/Q-wave MI/IDR 7 (1.5) 13 (2.6) 0.560 (0.222, 1.416)0.2204 Mortality/Q-wave MI/Stent 5 (1.0) 9 (1.8) 0.580 (0.193, 1.743)0.3320 thrombosis MITT Cangrelor Clopidogrel (N = 4347) (N = 4320) OR(95% CI) P Value Mortality/MI/IDR 308 (7.1) 293 (6.8) 1.049 (0.889,1.238) 0.5709 MI 292 (6.7) 264 (6.1) 1.107 (0.932, 1.315) 0.2451 IDR 19(0.4) 30 (0.7) 0.628 (0.353, 1.118) 0.1140 All-cause mortality 9 (0.2) 9(0.2) 0.995 (0.394, 2.508) 0.9910 Stent thrombosis 11 (0.3) 15 (0.3)0.729 (0.334, 1.588) 0.4261 Stroke 6 (0.1) 7 (0.2) 0.852 (0.286, 2.538)0.7742 Q-wave MI 4 (0.1) 10 (0.2) 0.397 (0.125, 1.268) 0.1190Mortality/Q-wave MI/IDR 30 (0.7) 45 (1.0) 0.661 (0.416, 1.051) 0.0801Mortality/Q-wave MI/Stent 23 (0.5) 31 (0.7) 0.737 (0.429, 1.265) 0.2681thrombosis MITT With STEMI Cangrelor Clopidogrel (N = 450) (N = 449) OR(95% CI) P Value Mortality/MI/IDR 18 (4.0) 17 (3.8) 1.064 (0.541, 2.092)0.8578 MI 14 (3.1) 8 (1.8) 1.778 (0.739, 4.282) 0.1991 IDR 6 (1.3) 7(1.6) 0.857 (0.286, 2.571) 0.7833 All-cause mortality 1 (0.2) 4 (0.9)0.249 (0.028, 2.235) 0.2143 Stent thrombosis 4 (0.9) 4 (0.9) 1.002(0.249, 4.033) 0.9975 Stroke 0 (0.0) 0 (0.0) — — Q-wave MI 0 (0.0) 0(0.0) — — Mortality/Q-wave MI/IDR 7 (1.6) 11 (2.5) 0.632 (0.243, 1.645)0.3473 Mortality/Q-wave MI/Stent 5 (1.1) 8 (1.8) 0.622 (0.202, 1.917)0.4084 thrombosis Safety Cangrelor Clopidogrel (N = 4374) (N = 4365) OR(95% CI) P Value Mortality/MI/IDR 310 (7.1) 294 (6.7) 1.058 (0.896,1.248) 0.5073 MI 294 (6.7) 265 (6.1) 1.116 (0.940, 1.325) 0.2091 IDR 19(0.4) 30 (0.7) 0.631 (0.355, 1.123) 0.1175 All-cause mortality 9 (0.2) 9(0.2) 0.999 (0.396, 2.519) 0.9984 Stent thrombosis 11 (0.3) 15 (0.3)0.732 (0.336, 1.595) 0.4326 Stroke 6 (0.1) 7 (0.2) 0.856 (0.288, 2.550)0.7803 Q-wave MI 4 (0.1) 10 (0.2) 0.399 (0.125, 1.273) 0.1207Mortality/Q-wave MI/IDR 30 (0.7) 45 (1.0) 0.664 (0.417, 1.056) 0.0834Mortality/Q-wave MI/Stent 23 (0.5) 31 (0.7) 0.740 (0.431, 1.271) 0.2751thrombosis Variables are presented as no. (%) unless otherwiseindicated. CI denotes confidence interval; IDR, ischemia-drivenrevascularization; ITT, intent to treat; MI, myocardial infarction;MITT, modified intent to treat; OR, odds ratio; STEMI, ST-segmentelevation myocardial infarction.

A substudy was conducted at 15 sites to evaluate platelet functionduring infusion and to assess whether the administration of a cangrelorinfusion prior to administration of clopidogrel 600 mg has any effect onplatelet inhibition by clopidogrel. Patients in the substudy wererequired to be clopidogrel naïve and could not have receivedglycoprotein IIb/IIIa inhibition during the procedure. Platelet functionparameters were measured using the VerifyNow P2Y₁₂ Assay (Accumetrics,San Diego, Calif.). Samples were taken before study drug administration,at approximately 2 hours (during cangrelor/placebo infusion), and 10hours or next day following randomization.

The median baseline P2Y₁₂ reaction units (PRU) from the VerifyNow P2Y₁₂assay were 335 in the cangrelor arm (264, 384; n=97) and 329 in theclopidogrel arm (285.5, 376.5; n=100). During the study drug infusion,the median PRU was significantly lower in the cangrelor arm (93.5; 40.0,173.5; n=64) compared with the clopidogrel arm during the same timeperiod (277; 206.0, 355.0; n=74). At 12-24 hours after discontinuationof the cangrelor infusion, the median PRU was 228 in the cangrelor arm(156.0, 298.0; n=87) and 206 in the clopidogrel arm (135.0, 274.0;n=87).

The results of this study demonstrated that the benefits of cangrelorinfusion were equivalent to those of 600 mg clopidogrel using thepredefined primary endpoint, although significantly higher levels ofperiprocedural platelet inhibition were achieved with cangrelor.

Example 3 Comparison of Cangrelor to Clopidogrel Standard of CareTherapy in Patients Who Require Percutaneous Coronary Intervention

The efficacy and safety of cangrelor versus clopidogrel standard of caretherapy was examined in patients with atherosclerosis undergoing PCI ina double-blind, placebo-controlled, double-dummy study.

A total of 11,145 patients underwent randomization at 153 sites in 12countries from Sep. 30, 2010 to Oct. 3, 2012. Randomization wasperformed before PCI with the use of an interactive voice-response orWeb-response system, with stratification according to site, baselinestatus (normal or abnormal, as defined by a combination of biomarkerlevels, electrocardiographic changes, and symptoms), and intendedloading dose of clopidogrel (600 mg or 300 mg). Randomization dividedthe patients into two groups: the cangrelor group and the clopidogrelgroup. Patients assigned to the cangrelor group were administered: (i)placebo capsules (before or immediately after PCI to match clopidogrelcapsules administered in the clopidogrel group); (ii) a cangrelor bolus(30 μg/kg)/infusion (4 μg/kg/min); and (iii) capsules containing 600 mgof clopidogrel administered at the end of infusion. Patients assigned tothe clopidogrel group were administered: (i) clopidogrel capsules (300mg or 600 mg before or immediately after PCI, with the dose and timingof administration determined at the discretion of the siteinvestigator); (ii) a placebo bolus/infusion (to match the cangrelorbolus/infusion administered in the cangrelor group); and (iii) placebocapsules administered at the end of the infusion (to match the capsulescontaining 600 mg of clopidogrel administered at the end of the infusionin the cangrelor group). The cangrelor or placebo infusion wasadministered for at least 2 hours or the duration of the PCI procedure,whichever was longer. A summary of the study design is shown in FIG. 7.

The protocol called for aspirin (75 to 325 mg) to be administered to allpatients. The protocol also called for a maintenance dose of clopidogrel(75 mg) to be administered during the first 48 hours afterrandomization; thereafter, clopidogrel or another P2Y₁₂ inhibitor couldbe administered at the discretion of the investigator, according tolocal guidelines. The choice of a periprocedural anticoagulant(bivalirudin, unfractionated heparin, low-molecular-weight heparin, orfondaparinux) was also at the discretion of the investigator.Glycoprotein IIb/IIIa inhibitors were allowed only as rescue therapyduring PCI to treat new or persistent thrombus formation, slow or noreflow, side-branch compromise, dissection, or distal embolization. Theinvestigator at the site determined the protocol for management of thearterial sheath.

The inclusion criteria for the trial were men or nonpregnant women, 18years of age or older with coronary atherosclerosis who required PCI forstable angina, a non-ST-segment elevation acute coronary syndrome, orST-segment elevation myocardial infarction (STEMI). Patients wererequired to provide written informed consent.

Major exclusion criteria were receipt of a P2Y₁₂ inhibitor or abciximabat any time in the 7 days before randomization and receipt ofeptifibatide or tirofiban or fibrinolytic therapy in the 12 hours beforerandomization.

The primary efficacy end point was the composite rate of death from anycause, myocardial infarction, IDR, or stent thrombosis in the 48 hoursafter randomization in the modified intention-to-treat population (whichcomprised patients who actually underwent PCI and received the studydrug). The protocol specified that if more than 15% of the patientsreceived a 300-mg loading dose of clopidogrel (as compared with a 600-mgdose) at the time of randomization, the primary analysis was to beadjusted for loading dose in addition to baseline status. The keysecondary end point was the incidence of stent thrombosis at 48 hours.This end point included definite stent thrombosis, defined according tothe criteria of the Academic Research Consortium, or intraproceduralstent thrombosis, which was assessed, with group assignments concealed,at an angiographic core laboratory (Cardiovascular Research Foundation).Intraprocedural stent thrombosis was defined as any new or worsenedthrombus related to the stent procedure that was confirmedangiographically. Events of death, myocardial infarction, IDR, and stentthrombosis that occurred during the first 30 days after randomizationwere adjudicated by the clinical events committee at the Duke ClinicalResearch Institute. The criteria that the clinical events committee usedto define myocardial infarction are provided in Tables 12A and 12B. Thestudy adhered to the universal definition of myocardial infarction formyocardial infarction unrelated to PCI but expanded on the definition ofPCI-related myocardial infarction.

TABLE 12A Baseline status assessment and trigger logic.* Cardiac MarkersIschemic Symptoms² (Troponin Preferred; use (Angina or equivalentBaseline Status CKMB if not available) ECG¹ (12 Lead) symptoms at rest)Baseline Normal (No MI at baseline) Stable angina/elective All sampleswithin 6 hours AND: no AND: no ongoing ACS prior to access sample arepresumed new symptoms or symptoms normal (1 sample sufficient; changeswithin 6 hours prior to access samples can be <6 hr apart) site sampleNSTE-ACS 2 normal samples ≧6 hours AND: no AND: no ongoing ACS apart(sample 2 is the access presumed new symptoms or symptoms sample)changes within 6 hours prior to access site sample Baseline Abnormal (MIongoing at baseline) Decreasing & returns to 2 samples ≧6 hours apartwith AND: no AND: no recent symptoms normal most recent access samplepresumed new within 6 hours prior to access returned to normal ECGchanges site sample Decreasing & remains 2 samples ≧6 hours apart withAND: no AND: no recent symptoms abnormal most recent access samplepresumed new within 6 hours prior to access fallen at least 20% ECGchanges site sample Increasing Insufficient biomarker data for OR:Presumed OR: recent symptoms within all other categories new changes 6hours prior to access site including STEMI sample Baseline unknown Nosamples pre PCI available *CKMB denotes creatine kinase-myocardial bandisoenzyme, ECG denotes electrocardiography, MI denotes myocardialinfarction, NSTE-ACS denotes non-ST-segment elevation acute coronarysyndrome, and STEMI denotes ST-segment elevation myocardial infarction.¹ECG changes: ST segment elevation/depression >0.1 mV (>1 mm) in atleast 2 contiguous leads; new LBBB; new Q wave (greater than 0.03seconds). ECG collection post PCI: within 1 hour after PCI;pre-discharge. ²Ischemic symptoms: angina or equivalent symptoms thatneed to be treated medically or lasting ≧20 min. Ischemic symptoms asdetermined by the treating physician include but are not limited toweakness, shortness of breath, wheezing, tiredness, fainting, sweating,nausea/vomiting, abdominal pain, back pain, jaw pain, palpitations, fastheartbeat, drug use for chest pain (nitroglycerin, morphine, betablocker, etc).

TABLE 12B Definition of PCI-related myocardial infarction.* EndpointNon-biomarker Evidence Biomarkers post PCI Definition Baseline MI statusof Ischemia (core lab CKMB¹ mass) MI Baseline normal Not required toqualify MI elevation ≧3x ULN Stable angina/NSTE-ACS ReinfarctionBaseline decreasing & returns Not required to qualify MI elevation ≧3xULN to normal (No intervening event from elevated sample to PCI)Baseline decreasing & remains (1 of 3): AND: Re-elevation of abnormalAngiographic complications² CKMB ≧3xULN and ≧50% (No intervening eventfrom OR elevated sample to PCI) Ischemic symptoms³ OR New ECG changes⁴Baseline abnormal & (2 of 2): AND: Re-elevation of increasing ORAngiographic complication CKMB ≧3x ULN and ≧50% Baseline unknown AND NewECG changes *MI denotes myocardial infarction, CKMB denotes creatinekinase-myocardial band isoenzyme, NSTE-ACS denotes non-ST-segmentelevation acute coronary syndrome, ULN denotes upper limit of normal,and PCI denotes percutaneous coronary intervention. ¹CKMB collectionpost PCI: 6 hourly collection through 24 hours (minimum of 3 samplesrequired). Core lab values take priority; hospital labs may be used ifcore lab not available (CKMB priority but troponin may be used).²Angiographic evidence of complication (assessed by the angiographiccore laboratory); New onset of vessel closure or compromise defined asTIMI 0/1 flow after baseline TIMI 2/3 flow (also termed acute closure orno reflow); or TIMI 2 flow after baseline TIMI 3 flow (also termed slowreflow); or Sustained distal embolization; or Sustained side-branchclosure of a vessel ≧2 mm in diameter; or Intra-Procedural ThromboticEvent (IPTE): new or worsening thrombus formation at any time during theprocedure. The occurrence of IPTE can be a stent related or not stentrelated complication phenomena or intra-procedural stent thrombosis(IPST) new or worsening thrombus related to the stent or abrupt closuredue to thrombosis. Abrupt closure due to non-thrombotic causes,including major dissections, perforation, or other etiologies, will notbe considered IPST. If a non- thrombotic cause of abrupt stent closurecannot be definitively determined, the cause will be considered IPST.IPST may present as either acute thrombotic stent closure after a stentwas implanted in a patient with a patent vessel beforehand, or newthrombus formation within or adjacent to a stent in a vessel in whichthrombus either was not present or had diminished or resolved before thestent was implanted. ³Ischemic symptoms: angina or equivalent symptomsthat need to be treated medically or lasting ≧20 min. Ischemic symptomsas determined by the treating physician include but are not limited toweakness, shortness of breath, wheezing, tiredness, fainting, sweating,nausea/vomiting, abdominal pain, back pain, jaw pain, palpitations, fastheartbeat, drug use for chest pain (nitroglycerin, morphine, betablocker, etc.). ⁴ECG changes: ST segment elevation/depression >0.1 mV(>1 mm) in at least 2 contiguous leads; new LBBB; new Q wave (greaterthan 0.03 seconds). ECG collection post PCI: within 1 hour after PCI;pre-discharge.

The primary safety end point was severe bleeding not related tocoronary-artery bypass grafting, according to the Global Use ofStrategies to Open Occluded Coronary Arteries (GUSTO) criteria, at 48hours. Several other bleeding definitions were also applied.

On the basis of prior studies, it was assumed that the rate of thecomposite primary end point would be 5.1% in the clopidogrel group and3.9% in the cangrelor group, representing a 24.5% reduction in the oddsratio with cangrelor. It was estimated that approximately 10,900patients would need to be enrolled for the study to have 85% power todetect that reduction. A two-sided overall alpha level of 0.05 was usedfor all analyses. This study had an adaptive design with conditionalpower calculation and potential for reestimation of the sample size, ifnecessary, after the interim analysis that was scheduled to be performedafter 70% of the patients were enrolled.

The numbers and percentages of patients within each analysis population(modified intention-to-treat, intention-to-treat, and safety) weresummarized according to treatment group. The primary efficacy analysisof the rate of the composite end point of death from any cause,myocardial infarction, IDR, or stent thrombosis (with all eventsadjudicated by the clinical events committee) in the 48 hours afterrandomization was conducted in the modified intention-to-treatpopulation. The primary safety analysis was conducted in the safetypopulation, which comprised all patients who underwent randomization andreceived at least one dose of the study drug; patients were classifiedaccording to the actual treatment received. All calculations andstatistical analyses were performed with the use of SAS software,version 9.2.

Of the 11,145 patients who underwent randomization, 203 did not undergoPCI or did not receive a study drug; therefore, the modifiedintention-to-treat population comprised 10,942 patients (FIG. 8). Thebaseline characteristics were well balanced between the two groups. Thecharacteristics of the patients and the procedure are shown in Tables 13and 14.

TABLE 13 Baseline characteristics of the patients and characteristics ofthe procedure in the modified intention-to-treat population, accordingto treatment group.* Cangrelor Clopidogrel Characteristic (N = 5472) (N= 5470) Age - yr Median 64.0 64.0 Interquartile range 56-72 56-72 Femalesex - no. (%) 1558 (28.5) 1493 (27.3) White race - no./total no. (%)†5132/5469 (93.8) 5120/5463 (93.7) Weight - kg Median 84.0 84.0Interquartile range 73-95 74-96 Diagnosis at presentation - no. (%)Stable angina 3121 (57.0) 3019 (55.2) NSTE-ACS 1389 (25.4) 1421 (26.0)STEMI 962 (17.6) 1030 (18.8) Region - no. (%) United States 2048 (37.4)2049 (37.5) Other countries 3424 (62.6) 3421 (62.5) Cardiac-biomarkerstatus - no./total no. (%)‡ Normal 3520/5467 (64.4) 3432/5466 (62.8)Abnormal 1947/5467 (35.6) 2034/5466 (37.2) Medical history - no./totalno (%) Diabetes mellitus 1519/5464 (27.8) 1536/5463 (28.1) Currentsmoker 1504/5339 (28.2) 1549/5339 (29.0) Hypertension 4374/5459 (80.1)4332/5454 (79.4) Hyperlipidemia 3363/4851 (69.3) 3338/4836 (69.0) Priorstroke or TIA 271/5455 (5.0) 244/5452 (4.5) Prior myocardial infarction1092/5441 (20.1) 1175/5431 (21.6) PTCA or PCI 1268/5462 (23.2) 1333/5461(24.4) CABG 578/5466 (10.6) 500/5464 (9.2) Congestive heart failure552/5460 (10.1) 584/5456 (10.7) Peripheral artery disease 447/5407 (8.3)385/5419 (7.1) Periprocedural medications - no./total no. (%)Clopidogrel, 300-mg loading dose 1405/5472 (25.7) 1401/5470 (25.6)Clopidogrel, 600-mg loading dose 4067/5472 (74.3) 4069/5470 (74.4)Bivalirudin 1252/5472 (22.9) 1269/5468 (23.2) Unfractionated heparin4272/5472 (78.1) 4276/5469 (78.2) Low-molecular-weight heparin 732/5472(13.4) 753/5468 (13.8) Fondaparinux 156/5471 (2.9) 135/5470 (2.5)Aspirin 5164/5469 (94.4) 5148/5465 (94.2) Duration of PCI - min Median18   17   Interquartile range 10-30 10-30 Drug-eluting stent - no. (%)3061 (55.9) 3020 (55.2) Bare-metal stent - no. (%) 2308 (42.2) 2344(42.9) Balloon angioplasty - no. (%) 292 (5.3) 273 (5.0) *Denominatorsexclude patients in whom the status was reported as unknown by the studycenter. There were no significant differences between the two groups,except for a history of coronary-artery bypass grafting (CABG) (P =0.01), prior myocardial infarction (P = 0.04), and peripheral-arterydisease (P = 0.02). NSTE-ACS denotes non-ST-segment elevation acutecoronary syndrome, PCI percutaneous coronary intervention, PTCApercutaneous transluminal coronary angioplasty, STEMI ST-segmentelevation myocardial infarction, and TIA transient ischemic attack.†Race was self-reported. ‡Cardiac biomarker status was considered to beabnormal if at least one of the baseline troponin 1 or T levels,obtained within 72 hours before randomization or after randomization butbefore initiation of the study drug, was greater than the upper limit ofthe normal range, as determined by the local laboratory. If the baselinetroponin level was not available, the baseline MB fraction of creatinekinase was used.

TABLE 14 Additional baseline and procedural characteristics for themodified intention-to-treat population, according to the treatmentgroup.* Cangrelor Clopidogrel Characteristic (N = 5472) (N = 5470) Age≧65 years 2645/5472 (48.3) 2615/5470 (47.8) ≧75 years 1022/5472 (18.7)988/5470 (18.1) Sex, No. (%) Male 3914/5472 (71.5) 3977/5470 (72.7)Female 1558/5472 (28.5) 1493/5470 (27.3) Race, No. (%) White 5132/5469(93.8) 5120/5463 (93.7) Asian 171/5469 (3.1) 175/5463 (3.2) Black149/5469 (2.7) 146/5463 (2.7) Other 17/5469 (0.3) 22/5463 (0.4) Hispanicor Latino, 193/5472 (3.5) 196/5470 (3.6) No. (%) Height, cm 172.0 (165,178) 172.0 (165, 178) Diabetes Type, No. (%) IDDM 459/5464 (8.4)404/5463 (7.4) Non-IDDM 1020/5464 (18.7) 1108/5463 (20.3) Unknown Type40/5464 (0.7) 23/5463 (0.4) Family history of 2088/5120 (40.8) 2079/5115(40.6) CAD, No. (%) Catheter Access Site, No. (%) Femoral 4053/5472(74.1) 4011/5470 (73.3) Radial 1410/5472 (25.8) 1445/5470 (26.4)Brachial 9/5472 (0.2) 14/5470 (0.3) Number of vessels treated, indexPCI, No. (%) 0 49/5472 (0.9) 49/5470 (0.9) 1 4545/5472 (83.1) 4604/5470(84.2) 2 768/5472 (14.0) 723/5470 (13.2) 3 103/5472 (1.9) 89/5470 (1.6)4 7/5472 (0.1) 5/5470 (0.1) *Denominators exclude patients in whom thestatus was reported as unknown by the site. There were no significantdifferences between the two groups, except for type of diabetes (p <0.05). CAD denotes coronary artery disease; IDDM denotesinsulin-dependent diabetes mellitus; and MITT denotes modified intent totreat.

The results of the analyses of the efficacy and safety end points at 48hours after randomization are provided in Tables 15, 16, and 17.

The rate of the primary composite efficacy end point of death from anycause, myocardial infarction, IDR, or stent thrombosis at 48 hours wassignificantly lower in the cangrelor group than in the clopidogrel group(4.7% vs. 5.9%; odds ratio, 0.78; 95% confidence interval [CI], 0.66 to0.93; P=0.005), on the basis of the prespecified logistic-regressionanalysis, which adjusted for baseline status (normal vs. abnormal) andclopidogrel loading dose (600 mg vs. 300 mg) (Table 15). The result ofthe crude analysis was similar (odds ratio, 0.79; 95% CI, 0.67 to 0.93;P=0.006). FIG. 9A shows the Kaplan-Meier estimates of the time-to-eventdistributions for the primary end point. The number needed to treat withcangrelor to prevent one primary end-point event is 84 (95% CI, 49 to285).

The rate of the key secondary efficacy end point of stent thrombosis at48 hours was also lower in the cangrelor group than in the clopidogrelgroup (0.8% vs. 1.4%; odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01)(Table 15). FIG. 9B shows the Kaplan-Meier estimates of thetime-to-event distributions for the key secondary end point.

The rate of the primary safety end point, GUSTO-defined severe bleeding,was 0.16% in the cangrelor group as compared with 0.11% in theclopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44)(Table 15). Bleeding events according to several other bleedingdefinitions were also examined (Table 17). In a post hoc analysis, theprimary efficacy end point and the primary safety end point werecombined to provide a composite end point of the net rate of adverseclinical events, which was 4.8% in the cangrelor group as compared with6.0% in the clopidogrel group (odds ratio, 0.80; 95% CI, 0.68 to 0.94;P=0.008) (Table 15).

TABLE 15 Efficacy and safety end points at 48 hours afterrandomization.* Odds Ratio End Point Cangrelor Clopidogrel (95% Cl) PValue number/total number (percent) Efficacy No. of Patients in modifiedintention-to- 5472 5470 treat population Primary end point: death fromany cause, 257/5470 (4.7) 322/5469 (5.9) 0.78 (0.66-0.93) 0.005myocardial infarction, ischemia-driven revascularization, or stentthrombosis† Key secondary end point: stent thrombosis 46/5470 (0.8)74/5469 (1.4) 0.62 (0.43-0.90) 0.01 Myocardial infarction 207/5470 (3.8)255/5469 (4.7) 0.80 (0.67-0.97) 0.02 Q-wave myocardial infarction11/5470 (0.2) 18/5469 (0.3) 0.61 (0.29-1.29) 0.19 Ischemia-drivenrevascularization 28/5470 (0.5) 38/5469 (0.7) 0.74 (0.45-1.20) 0.22Death from any cause 18/5470 (0.3) 18/5469 (0.3) 1.00 (0.52-1.92) >0.999Death from cardiovascular causes 18/5470 (0.3) 18/5469 (0.3) 1.00(0.52-1.92) >0.999 Death or stent thrombosis 59/5470 (1.1) 87/5469 (1.6)0.67 (0.48-0.94) 0.02 Death, Q-wave myocardial infarction, or 49/5470(0.9) 64/5469 (1.2) 0.76 (0.53-1.11) 0.16 ischemia-drivenrevascularization Safety: non-CABG-related bleeding No. of patients insafety population 5529 5527 GUSTO-defined bleeding Primary safety endpoint: severe 9/5529 (0.2) 6/5527 (0.1) 1.50 (0.53-4.22) 0.44 orlife-threatening bleeding Moderate bleeding 22/5529 (0.4) 13/5527 (0.2)1.69 (0.85-3.37) 0.13 Severe or moderate bleeding 31/5529 (0.6) 19/5527(0.3) 1.63 (0.92-2.90) 0.09 TIMI-defined bleeding Major bleeding 5/5529(0.1) 5/5527 (0.1) 1.00 (0.29)-3.45) >0.999 Minor bleeding 9/5529 (0.2)3/5527 (0.1) 3.00 (0.81-11.10) 0.08 Major or minor bleeding 14/5529(0.3) 8/5527 (0.3) 1.75 (0.73-4.18) 0.20 Any blood transfusion 25/5529(0.5) 16/5527 (0.3) 1.56 (0.83-2.93) 0.16 Efficacy and safety: netadverse clinical events‡ Death, myocardial infarction, ischemia-264/5470 (4.8) 327/5469 (6.0) 0.80 (0.68-0.94) 0.008 drivenrevascularization, stent thrombosis, or GUSTO-defined severe bleeding*GUSTO denotes Global Use of Strategies to Open Occluded CoronaryArteries, and TIMI denotes Thrombolysis in Myocardial Infarction. †‘Theprespecified logistic-regression analysis was adjusted for baselinestatus (normal vs. abnormal) and clopidogrel loading dose (600 mg vs.300 mg). ‡The primary efficacy and primary safety end points werecombined to provide a composite end point of net adverse clinical eventsin the modified intention-to-treat population.

TABLE 16 Additional efficacy endpoints at 48 hours after randomizationfor the modified intention-to-treat population.* Cangrelor ClopidogrelEnd Point (N = 5472) (N = 5470) OR (95% CI) P Value Death/MI 220/5470(4.0) 272/5469 (5.0) 0.80 (0.67, 0.96) 0.02 Death/MI/ST 249/5470 (4.6)312/5469 (5.7) 0.79 (0.66, 0.94) 0.006 Death/MI/IDR 230/5470 (4.2)286/5469 (5.2) 0.80 (0.67, 0.95) 0.01 Death/MI/IDR/Definite ST 230/5470(4.2) 286/5469 (5.2) 0.80 (0.67, 0.95) 0.01 Death/MI/Definite ST222/5470 (4.1) 276/5469 (5.0) 0.80 (0.66, 0.95) 0.01 Definite ST 12/5470 (0.2)  22/5469 (0.4) 0.54 (0.27, 1.10) 0.09 *MI denotesmyocardial infarction, ST denotes stent thrombosis, and IDR denotesischemia-driven revascularization.

TABLE 17 Additional efficacy and safety endpoints at 48 hours afterrandomization.* Intention-to-Treat (ITT) Cangrelor Clopidogrel Ischemic(N = 5581) (N = 5564) OR (95% CI) P Value Death/MI/IDR/ST 260/5573 (4.7)325/5561 (5.8) 0.79 (0.67, 0.93) 0.005 Stent thrombosis 46/5573 (0.8)74/5561 (1.3) 0.62 (0.43, 0.89) 0.01 MI 207/5573 (3.7) 255/5561 (4.6)0.80 (0.67, 0.97) 0.02 Q-wave MI 11/5573 (0.2) 18/5561 (0.3) 0.61 (0.29,1.29) 0.19 IDR 29/5573 (0.5) 38/5561 (0.7) 0.76 (0.47, 1.23) 0.27 Death20/5573 (0.4) 21/5561 (0.4) 0.95 (0.51, 1.75) 0.87 CV Death 20/5573(0.4) 21/5561 (0.4) 0.95 (0.51, 1.75) 0.87 Death/ST 61/5573 (1.1)90/5561 (1.6) 0.67 (0.49, 0.93) 0.02 Death/MI 222/5573 (4.0) 275/5561(5.0) 0.80 (0.67, 0.96) 0.01 Death/MI/ST 251/5573 (4.5) 315/5561 (5.7)0.79 (0.66, 0.93) 0.005 Death/MI/IDR 233/5573 (4.2) 289/5561 (5.2) 0.80(0.67, 0.95) 0.01 Death/Q-wave MI/IDR 52/5573 (0.9) 67/5561 (1.2) 0.77(0.54, 1.11) 0.16 Death/MI/IDR/ST/GUSTO 267/5573 (4.8) 330/5561 (5.9)0.80 (0.68, 0.94) 0.007 Severe Bleeding (Net Adverse Clinical Events,NACE) Safety Non-CABG Related Cangrelor Clopidogrel Bleeding (N = 5529)(N = 5527) OR (95% CI) P Value ACUITY criteria Major bleeding 235/5529(4.3) 139/5527 (2.5) 1.72 (1.39, 2.13) <0.001 Major without ≧5 cm42/5529 (0.8) 26/5527 (0.5) 1.62 (0.99, 2.64) 0.05 hematoma Minorbleeding 653/5529 (11.8) 475/5527 (8.6) 1.42 (1.26, 1.61) <0.001 BARCcriteria* Type 3 22/5529 (0.4) 13/5527 (0.2) 1.69 (0.85, 3.37) 0.13 Type3a 11/5529 (0.2) 4/5527 (0.1) 2.75 (0.88, 8.65) 0.07 Type 3b 9/5529(0.2) 8/5527 (0.1) 1.12 (0.43, 2.92) 0.81 Type 3c 2/5529 (0.0) 1/5527(0.0) 2.00 (0.18, 22.06) 0.56 *MI denotes myocardial infarction, STdenotes stent thrombosis, and IDR denotes ischemia-drivenrevascularization, CV denotes cardiovascular. GUSTO denotes Global Useof Strategies to Open Occluded Coronary Arteries, ACUITY denotes AcuteCatheterization and Urgent Intervention Triage Strategy trial, and BARCdenotes Bleeding Academic Research Consortium.

The rate of intraprocedural stent thrombosis was lower in the cangrelorgroup than in the clopidogrel group (0.6% vs. 1.0%; odds ratio, 0.65;95% CI, 0.42 to 0.99; P=0.04). The use of rescue therapy with aglycoprotein IIb/IIIa inhibitor was 2.3% with cangrelor as compared with3.5% with clopidogrel (odds ratio, 0.65; 95% CI, 0.52 to 0.82; P<0.001).The rate of procedural complications was lower with cangrelor than withclopidogrel (3.4% vs. 4.5%; odds ratio, 0.74; 95% CI, 0.61 to 0.90;P=0.002).

At 30 days, the rate of the composite efficacy end point remainedsignificantly lower in the cangrelor group than in the clopidogrel group(6.0% vs. 7.0%; odds ratio, 0.85; 95% CI, 0.73 to 0.99; P=0.03); therelative reduction in stent thrombosis also persisted (1.3% vs. 1.9%;odds ratio, 0.68; 95% CI, 0.50 to 0.92; P=0.01) (Table 18).

TABLE 18 Efficacy outcomes at 30 days after randomization. Odds RatioEnd Points Cangrelor Clopidogrel (95% Cl) P Value number/total number(percent) No. of Patients in modified intention-to- 5472 5470 treatpopulation Death from any cause, myocardial 326/5462 (6.0)  380/5457(7.0)  0.85 (0.73-0.99) 0.03 infarction, ischemia-drivenrevascularization, or stent thrombosis† Stent thrombosis 71/5462 (1.3)104/5457 (1.9)  0.68 (0.50-0.92) 0.01 Myocardial infarction 225/5462(4.1)  272/5457 (5.0)  0.82 (0.68-0.98) 0.03 Q-wave myocardialinfarction 14/5462 (0.3) 22/5457 (0.4) 0.63 (0.32-1.24) 0.18Ischemia-driven revascularization 56/5462 (1.0) 66/5457 (1.2) 0.85(0.59-1.21) 0.36 Death from any cause 60/5462 (1.1) 55/5457 (1.0) 1.09(0.76-1.58) 0.64 Death from cardiovascular causes 48/5462 (0.9) 46/5457(0.8) 1.04 (0.69-1.57) 0.84 †‘The prespecified logistic-regressionanalysis was adjusted for baseline biomarker status (normal vs.abnormal) and clopidogrel loading dose (600-mg vs. 300-mg).

The rate of adverse events related to treatment was similar in thecangrelor and clopidogrel groups (20.2% and 19.1%, respectively;P=0.13); 0.5% of these adverse events in the cangrelor group and 0.4% ofthose in the clopidogrel group led to discontinuation of the study drug(P=0.21). There were significantly more cases of transient dyspnea withcangrelor than with clopidogrel (1.2% vs. 0.3%, P<0.001) (Table 19).

TABLE 19 Statistically significant treatment emergent adverse events at48 hours after randomization (safety population). Fisher System OrganClass Cangrelor Clopidogrel Chi-square exact Preferred Term (N = 5529)(N = 5527) P value P value Psychiatric disorders Agitation 11/5529 (0.2) 3/5527 (0.1) 0.03 0.06 Gastrointestinal disorders Diarrhea 15/5529(0.3)  6/5527 (0.1) 0.05 0.08 General disorders and administration siteconditions Chest Pain 55/5529 (1.0) 93/5527 (1.7) 0.002 0.002Respiratory, thoracic, and mediastinal disorders Dyspnea 64/5529 (1.2)18/5527 (0.3) <0.001 <0.001 Injury, poisoning, and proceduralcomplications Procedural Pain  4/5529 (0.1) 12/5527 (0.2) 0.05 0.05 Pvalues not adjusted for multiple comparisons.

The reduction in the primary efficacy end point with cangrelor wasconsistent across multiple subgroups, with no significant interactionswith baseline variables except for status with respect to a history ofperipheral-artery disease. The benefit with cangrelor was similar amongpatients presenting with STEMI, those presenting with non-ST-segmentelevation acute coronary syndrome, and those presenting with stableangina. There was no heterogeneity of treatment effect between patientsin the United States and those in other countries (P=0.26) (FIG. 10).

According to the protocol, patients received a loading dose ofclopidogrel or placebo after their coronary anatomy was delineated. Themajority of patients received the loading dose before PCI was started(63.4%). The rest of the patients received the loading dose in thecatheterization laboratory before PCI was completed (6.4%), within 1hour after PCI was completed (30.1%), or more than 1 hour after PCI wascompleted (0.1%). There was no significant difference in the effect ofcangrelor on the primary end point between patients who received theloading dose immediately before PCI (odds ratio, 0.80; 95% CI, 0.64 to0.98) and those who received it during or after PCI (odds ratio, 0.79;95% CI, 0.59 to 1.06) (P=0.99 for interaction). Similarly, there was nosignificant difference in the effect of cangrelor on the primary endpoint between patients who received a 600-mg loading dose of clopidogrel(74.4% of the population) and those who received a 300-mg loading dose(25.6% of the population): the odds ratio for the primary end point withcangrelor was 0.77 (95% CI, 0.63 to 0.94) with the 600-mg loading doseand 0.84 (95% CI, 0.62 to 1.14) with the 300-mg loading dose (P=0.62 forinteraction). The protocol required at least 2 hours of study-druginfusion; the median duration of infusion in the cangrelor group was 129minutes (interquartile range, 120 to 146); the duration of infusion wassimilar in the clopidogrel group (in which patients received a placeboinfusion). A subgroup analysis showed a similar effect of cangreloramong patients who received the infusion for 129 minutes or less (oddsratio, 0.85; 95% CI, 0.68 to 1.07) and those who received the infusionfor more than 129 minutes (odds ratio, 0.72; 95% CI, 0.56 to 0.92)(P=0.31 for interaction) (FIG. 10).

Since the rate of the primary safety end point, GUSTO-defined severebleeding, was very low, severe bleeding according to GUSTO criteria wascombined with moderate bleeding to provide a larger number of events foran analysis of potential subgroup interactions. There were nointeractions at P<0.05 (FIG. 11).

As compared with clopidogrel administered immediately before or afterPCI, intravenous ADP-receptor blockade with cangrelor significantlyreduced the rate of periprocedural complications of PCI, including stentthrombosis. A reduction in the rate of acute periprocedural myocardialinfarction accounted for most of the benefit. The odds of an ischemicevent were 22% lower with cangrelor than with clopidogrel, and thisbenefit was not accompanied by a significant increase in severe bleedingor in the need for transfusions. In addition, the odds of stentthrombosis were 38% lower with cangrelor than with clopidogrel. The useof cangrelor resulted in a reduction in ischemic complications acrossthe full spectrum of patients undergoing contemporary PCI, with aconsistent benefit in major subgroups.

Example 1 and Example 2 suggested a clinical benefit of cangrelor,including a significant reduction in the secondary end point of stentthrombosis. However, the rate of the primary end point was not reducedin the previous examples, probably because the definition ofperiprocedural myocardial infarction in those studies did not allowdiscrimination of reinfarction in patients presenting for PCI soon afteradmission with a biomarker-positive acute coronary syndrome. In thetrial described in Example 3, the definition of periproceduralmyocardial infarction required careful assessment of patients' baselinebiomarker status. In addition, the use of an angiographic corelaboratory allowed objective determination of intraproceduralcomplications. Table 20 lists the differences between the trialsdescribed in Example 1/Example 2 and the trial described in Example 3.

TABLE 20 Differences between the study of Example 3 and the studies ofExamples 1 and 2.*† Examples 1 and 2 Example 3 Patient 70% Troponin (Tn)elevated at baseline Assumed 35% Tn elevated at baseline populationClopidogrel maintenance (PCI only) P2Y₁₂ inhibitor naive PCI requiredwith following: PCI required (Stable angina, NSTE-ACS, STEMI) STEMI:safety only (PCI) NSTEMI: Tn elevated Unstable angina: ECG changes andpain and age/diabetes Stable angina: capped (15%) Comparator 600 mgclopidogrel 300 mg or 600 mg (per hospital standard of care) End pointPrimary: Death/MI/IDR at 48 hr Primary: Death/MI/IDR/ST at 48 hr KeySecondary: ST at 48 hr Myocardial Not UDMI: reliance on cardiac UDMIimplemented: reliance on cardiac markers infarction markers alone todefine PCI MI and other evidence of ischemia to define PCI MI definition1 baseline sample 2 baseline samples at least 6 hours apart Biomarkernormal at baseline: MI required in NSTE-ACS patients to confirm definedas CKMB ≧3x ULN post resolving MI at baseline PCI Baseline normalpatients: MI defined as Biomarker elevated at baseline: CKMB ≧3x ULNpost PCI elevation in CKMB ≧3x ULN and Baseline abnormal patients wereclassified 50% increase from baseline into MI increasing or decreasingat baseline: sample or ECG changes Increasing: re-elevation in CKMB postPCI (≧3xULN and 50% increase from baseline) + additional evidence ofischemia (2 of 2): ECG changes AND angiographic evidence Decreasing:re-elevation in CKMB post PCI (≧3xULN and 50% increase from baseline) +additional evidence of ischemia (1 of 3): ischemic symptoms, ECG changesor angiographic evidence Stent Non-standard definition in IDR patientsARC definition in patients thrombosis but confirmed by CEC usingangiographic IPST (Intra-procedural stent thrombosis) = any definitionsource data procedural new or worsened thrombus related to the stentbased on angiographic evidence Statistics Event rate placebo: 7.7%;Assumed Event rate placebo: 5.1%; Effect size: 22.5-25% Assumed Effectsize: 24.5% *PCI denotes percutaneous coronary intervention, STEMIdenotes ST-segment elevation myocardial infarction, NSTEMI denotesnon-ST-elevated myocardial infarction, ECG denotes denoteselectrocardiography, NSTE-ACS denotes non-ST-segment elevation acutecoronary syndrome, MI denotes myocardial infarction, IDR denotesischemia-driven revascularization, ST denotes stent thrombosis. UDMIdenotes universal definition of myocardial infarction, CKMB denotescreatine kinase- myocardial band isoenzyme, and ULN denotes upper limitof normal. †Bhatt DL, et al. N Engl J Med 2009; 361 2330-41. HarringtonRA, et al. N Engl J Med 2009; 361 2318-29 White HD, Am Heart J 2012;163: 182-190.e4 Thygesen, J Am Coll Cardiol 2007; 50: 2173-95.

Having thus described in detail embodiments of the present invention, itis to be understood that the invention defined by the above paragraphsis not to be limited to particular details set forth in the abovedescription as many apparent variations thereof are possible withoutdeparting from the spirit or scope of the present invention.

What is claimed is:
 1. A method of treating, reducing the incidence of,or preventing an ischemic event in a patient undergoing percutaneouscoronary intervention (PCI), comprising administering to the patient apharmaceutical composition comprising cangrelor.
 2. The method of claim1, wherein the method treats, reduces the incidence of, or prevents anischemic event during PCI.
 3. The method of claim 1, wherein the methodtreats, reduces the incidence of, or prevents an ischemic event afterPCI.
 4. The method of claim 1, wherein the ischemic event is selectedfrom the group consisting of stent thrombosis, myocardial infarction,ischemia-driven revascularization, and mortality.
 5. The method of claim4, wherein the ischemic event is stent thrombosis.
 6. The method ofclaim 5, wherein the stent thrombosis is intraprocedural stentthrombosis.
 7. The method of claim 1, wherein the pharmaceuticalcomposition is administered to the patient before PCI, during PCI, afterPCI, or a combination thereof.
 8. The method of claim 1, wherein thepharmaceutical composition is administered to the patient intravenously.9. The method of claim 8, wherein the pharmaceutical composition isadministered as a bolus, as a continuous infusion, or as a bolusfollowed by a continuous infusion.
 10. The method of claim 9, whereinthe bolus comprises cangrelor in a dose of about 20 μg/kg to about 40μg/kg.
 11. The method of claim 10, wherein the continuous infusioncomprises cangrelor in a dose of about 1 μg/kg/min to about 10μg/kg/min.
 12. The method of claim 9, wherein the continuous infusion isadministered for the longer of (a) duration of the PCI, or (b) at leastabout 2 hours.
 13. The method of claim 1, wherein the administration ofthe pharmaceutical composition to the patient is not accompanied by asignificant increase in severe bleeding or the need for transfusions.14. The method of claim 1, wherein the PCI comprises stent implantation.15. A method of treating, reducing the incidence of, or preventing anischemic event in a patient undergoing PCI, comprising administering tothe patient (i) a pharmaceutical composition comprising cangrelor, and(ii) a P2Y₁₂ inhibitor.
 16. The method of claim 15, wherein the methodtreats, reduces the incidence of, or prevents an ischemic event duringPCI.
 17. The method of claim 15, wherein the method treats, reduces theincidence of, or prevents an ischemic event after PCI.
 18. The method ofclaim 15, wherein the P2Y₁₂ inhibitor is selected from the groupconsisting of clopidogrel, prasugrel, and ticagrelor.
 19. The method ofclaim 18, wherein the P2Y₁₂ inhibitor is clopidogrel.
 20. The method ofclaim 19, wherein the clopidogrel is administered after administrationof the pharmaceutical composition.